U.S. Route 22 (US 22) is a major east–west route and one of the original United States Numbered Highways, founded in 1926. It runs from Cincinnati, Ohio, at US 27, US 42, US 127, and US 52 to Newark, New Jersey, at US 1/9 at the Newark Airport Interchange.

US 22 is named the William Penn Highway through most of Pennsylvania. In southwest Ohio, it overlaps with State Route 3 (SR 3) and is familiarly known as the 3-C Highway, "22 and 3", and Montgomery Road.

A section of US 22 in Pennsylvania between New Alexandria at US 119 and Harrisburg at Interstate 81 (I-81) has been designated a part of Corridor M of the Appalachian Development Highway System.

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Lengths

	mi	km
OH	244.10	392.84
WV	6.01	9.67
PA	338.20	544.28
NJ	60.53	97.41
Total	648.84	1,044.21

US 22 has its westernmost endpoint in downtown Cincinnati. Its eastbound and westbound endpoints are not at the same intersection. Officially, US 22 eastbound begins on Central Avenue (US 27 northbound/US 52 westbound/US 127 northbound) at 5th Street, then proceeds north, turning east onto 7th Street. Meanwhile, US 22 westbound follows 9th Street and officially ends at Central Avenue (signage designating the end occurs much sooner, approaching Elm Street, US 42 northbound).

From downtown Cincinnati to Washington Court House, US 22 roughly follows the historic 3-C Highway which connected Cincinnati, Columbus, and Cleveland. This section is also concurrent with SR 3. At Washington Court House, SR 3 and US 22 diverge. US 22 continues to the east through Circleville to Lancaster. From Lancaster to Zanesville, US 22 roughly follows the route of Zane's Trace, an early pioneer road blazed by Ebenezer Zane beginning in 1796.

Starting just west of Cadiz, US 22 becomes a limited-access expressway for the remainder of its approximately 30 miles (48 km) in Ohio as it approaches and enters Greater Pittsburgh (with the exception of an at-grade intersection with no stoplights or signs on US 22 and narrowing to two lanes for about a mile (1.6 km) east of Cadiz). It junctions with SR 7 for roughly a mile (1.6 km) along the Ohio River shoreline in Steubenville.

Known as the Robert C. Byrd Expressway, the expressway route that began roughly 30 miles (48 km) to the west near Cadiz, Ohio, continues for approximately five miles (8.0 km) within the state of West Virginia (the highway runs concurrent with West Virginia Route 2, or WV 2, for one of those miles, or 1.6 km) as it approaches more population density within Greater Pittsburgh. US 22 travels through or borders the city of Weirton for its entire length in West Virginia, from the Ohio state line over the Ohio River, to the Pennsylvania state line.

US 22 enters Pennsylvania as a limited-access highway connecting Weirton, West Virginia, and Steubenville, Ohio, with Pittsburgh. Through much of Greater Pittsburgh, it overlaps I-376 and US 30. US 30 merges with US 22 near Imperial and Pittsburgh International Airport, and both highways then merge with I-376 in Robinson Township. Together, these three highways form a busy, limited-access multiplex through the city of Pittsburgh. US 30 then splits from I-376 and US 22 in Wilkinsburg, and the I-376/US 22 concurrency continues to the Pennsylvania Turnpike in Monroeville, where I-376 ends.

East of I-376, US 22 continues east of Pittsburgh as a primary arterial highway. The entire length between Pittsburgh and US 220 and I-99 just west of Altoona was widened to at least four lanes by mid-2011. I-99 links the highway to State College and the Pennsylvania Turnpike. Heading east from I-99, US 22 narrows and becomes the primary highway linking Hollidaysburg and Huntingdon. Near Mount Union, it forms a concurrency with US 522, and the two highways go northeast along the Juniata River to Lewistown.

In Lewistown, US 22 breaks with US 522 and forms a concurrency with US 322, and the two routes travel southeast, mostly as an expressway, toward Harrisburg. At the north end of Harrisburg, US 22 and US 322 split and US 22 runs southward toward the Pennsylvania Farm Show Complex & Expo Center. From there, it turns eastward along Arsenal Boulevard, Herr Street, and Walnut Street to Jonestown Road. Through Dauphin and Lebanon counties, US 22 parallels I-81 and I-78 to the south as a four-lane arterial. East of Fredericksburg, along the border between Lebanon and Berks counties, US 22 forms a concurrency with I-78, which runs to the Allentown area. Former highway alignments of US 22 that parallel this section are collectively known as the "Hex Highway", so called because of the Berks County-based Pennsylvania Dutch families that hang hex signs on their barns.

In the Lehigh Valley, US 22 is a four-lane limited-access expressway between Easton and I-78 to the west; it is dually designated with the Lehigh Valley Thruway in Allentown. The original designation for this expressway was to be I-78, but local opposition to a freeway in Phillipsburg, along with substandard conditions at Easton, forced federal highway officials to relocate I-78 south of Allentown, Bethlehem, Easton, and Phillipsburg. US 22 then crosses the Delaware River on the Easton–Phillipsburg Toll Bridge.

US 22 in New Jersey predates and was largely replaced by I-78 after I-78 was built between 1956 and 1989 and shares designation with I-78 from exit 3 to exit 18. US 22 was an expressway in some segments, including the area around Perryville and Clinton. It connects Phillipsburg with Newark in New Jersey.

US 22 has one major interchange besides I-78, that being I-287, although it is not a full interchange, with two missing movements: US 22 eastbound to I-287 northbound and I-287 southbound to US 22 westbound.

One of two level crossing of the highway happens in Union County in the Union Township section of the highway (the other occurring in Lewistown, Pennsylvania). It once belonged to the Rahway Valley Railroad; the crossing was closed in 1992 when service on the railroad was ended.

US 22 is one of the original U.S. Highways. In the 1925 plan, it was initially designed to terminate in Cleveland, Ohio, entering Ohio on modern US 422. In the finalized 1926 plan, however, it followed the current course to US 40, where it ended. In 1932, it was extended to Cincinnati as it is currently, replacing SR 10 and following preexisting SR 3.

Before the Byrd Expressway, West Virginia's segment of US 22 ran from Pennsylvania Avenue at the West Virginia–Pennsylvania state line to Main Street, then left on Main Street through downtown Weirton (aligning US 22 with WV 2), and right on Freedom Way to the Fort Steuben Bridge and Ohio River to Steubenville, Ohio. US 22 Alternate (US 22 Alt.) ran along Cove Road from Pennsylvania Avenue to the intersection of Harmon Creek Road (left turn) and the continuation of Cove Road.

With the opening of the first segment of the Byrd Expressway on March 9, 1972, US 22 was reassigned, starting on the new road from the West Virginia–Pennsylvania state line, continuing on Cove Road where the expressway ended and joining the remainder of the original route at Main Street. The Pennsylvania Avenue segment of US 22 from Colliers Way to Main Street was reassigned as WV 105 and US 22 Alt. was reassigned as WV 507. In 2003, WV 507 was extended along the previous US 22 alignment from Cove Road to the Fort Steuben Bridge and was reassigned as CR 507. The Fort Steuben Bridge, which originally carried US 22 across the Ohio River until the construction of the Veterans Memorial Bridge, was permanently closed on January 8, 2009, and demolished by detonation on February 21, 2012.

State	County	Location	mi	km	Exit	Destinations	Notes
Ohio	Hamilton	Cincinnati	0.00	0.00		US 27 south / US 42 south / US 52 east / US 127 south (Central Avenue) / 5th Street West	Western terminus of US 27 / US 42 south / US 52 / US 127 concurrency; southern terminus of SR 3
			0.09	0.14		US 50 west / SR 264 west (Sixth Street West) / I-75 north	Eastern terminus of SR 264; western terminus of one-way pair; exit 1E on I-75 south
			0.17	0.27		US 27 north / US 52 west / US 127 north (Central Avenue) / 7th Street West	Eastern terminus of US 27 / US 42 south / US 52 / US 127 concurrency
			0.33	0.53		Elm Street (US 42 north)
			0.87	1.40		Broadway Street	Eastern terminus of one-way pair
			1.26	2.03		I-71 north – Columbus	Northbound exit only; exit 2B on I-71 south
			1.58	2.54		Elsinore Place to I-471 / I-71 north	To US 42
			1.89	3.04		Eden Park Drive to I-471 / I-71 south
			4.49	7.23		I-71 south – Louisville	Exit 5 on I-71 north
		Norwood	5.93	9.54		SR 561 south (Sherman Avenue)	Western terminus of SR 561 concurrency
			6.25	10.06		SR 562 to I-75 / I-71	Exit 3 on SR 562 (Norwood Lateral Expressway); access via Norwood Avenue
			6.46	10.40		SR 561 north (Ross Avenue)	Eastern terminus of SR 561 concurrency
		Kenwood	11.41	18.36		I-71 – Columbus, Cincinnati	Exit 12 on I-71
		Montgomery	13.30	21.40		SR 126 west (Ronald Reagan Highway)	Roundabout; western terminus of SR 126 concurrency
			13.70	22.05		SR 126 east (Remington Road)	Eastern terminus of SR 126 concurrency
			16.15	25.99		I-275 to I-71 / SR 32 – Kentucky	Exit 50 on I-275
	Warren	Hopkinsville	24.64	39.65		SR 48 – South Lebanon, Maineville
		Morrow	29.97	48.23		SR 123 north – Lebanon	Western terminus of SR 123 concurrency
		Salem Township	31.70	51.02		SR 123 south – Blanchester	Eastern terminus of SR 123 concurrency
		Washington Township	37.54	60.41		SR 350 – Fort Ancient
	Clinton	Adams Township	41.66	67.05		SR 380 north – Xenia	Southern terminus of SR 380
		Wilmington	48.00	77.25		US 68 / SR 134 (South Street)
		Union Township	51.10	82.24		SR 73 to I-71 south – Hillsboro, Waynesville	Interchange
		Reesville	56.75	91.33		SR 72 – Highland, Jamestown
		Sabina	58.89	94.77		SR 729 (Howard Street)
	Fayette	Washington Court House	68.52	110.27		US 35 to I-71 – Dayton, Chillicothe, Fairgrounds	Exit 82 on US 35; access via collector-distributor roads
			69.69	112.16		US 62 west (Leesburg Avenue) / SR 41 south (Highland Avenue)	Western terminus of US 62 / SR 41 concurrency
			70.08	112.78		SR 41 north (North Street)	Eastern terminus of SR 41 concurrency
			70.32	113.17		US 62 west / SR 3 north (Columbus Avenue)	Eastern terminus of US 62 / SR 3 concurrency
			72.39	116.50		SR 753 to US 35 Byp.
	Pickaway	Atlanta	83.10	133.74		SR 207 – Mount Sterling, Deer Creek, Chillicothe
		Wayne Township	92.40	148.70		SR 138 west – Clarksburg	Eastern terminus of SR 138
			94.20	151.60		SR 104 – Columbus, Chillicothe
			95.62	153.89		SR 56 west – Mount London, London	Western terminus of SR 56 concurrency
		Circleville	96.79	155.77		US 23 – Columbus, Chillicothe	Interchange
			97.18	156.40		SR 188 east (Court Street)	Western terminus of SR 188
			97.83	157.44		SR 56 east (Main Street)	Eastern terminus of SR 56 concurrency
	Pickaway–Fairfield county line	Washington–Clearcreek township line	103.53	166.62		SR 674 north	Southern terminus of SR 674
	Fairfield	Hocking Township	113.09	182.00		SR 159 south – Tarlton	Northern terminus of SR 159
			114.16	183.72		US 33 – Logan, Columbus	Interchange
		Lancaster	117.14	188.52		SR 188 west (Cedar Hill Road)	Western terminus of SR 188 concurrency
			117.64	189.32		SR 158 north (Columbus Street)	Southern terminus of SR 158
			117.93	189.79		SR 37 west (High Street)	Western terminus of SR 37 concurrency
			118.77	191.14		SR 188 east (Cherry Street)	Eastern terminus of SR 188 concurrency
			121.58	195.66		SR 37 east – Bremen, Junction City, New Lexington	Eastern terminus of SR 37 concurrency
		Rushville	127.92	205.87		SR 664 to SR 256 – Bremen
	Perry	Somerset	135.61	218.24		SR 668 south	Western terminus of SR 668 concurrency
			135.78	218.52		SR 13 (Columbus Street)	Traffic circle
			136.37	219.47		SR 668 north – Brownsville, Flint Ridge	Eastern terminus of SR 668 concurrency
		Madison Township	141.70	228.04		SR 204 west – Millersport	Eastern terminus of SR 240
	Muskingum	East Fultonham	146.35	235.53		SR 345 south – East Fultonham, New Lexington, Perry State Forest	Northern terminus of SR 345
		Newton Township	150.30	241.88		SR 93 south – Roseville, Crooksville	Western terminus of SR 93 concurrency
		South Zanesville	153.62	247.23		SR 719 east to SR 60 / SR 146 / SR 555	Western terminus of SR 719
		Zanesville	155.87	250.85		US 40 west (Main Street)	Western terminus of US 40 concurrency
			155.93	250.95		SR 60 south / SR 146 east (9th Street) to I-70	Western terminus of SR 60 / SR 146 concurrency
			156.05	251.14		SR 60 north / SR 146 west (Underwood Street)	Eastern terminus of SR 60 / SR 146 concurrency
		Pleasant Grove	158.43	254.97		SR 93 north	Eastern terminus of SR 93 concurrency
		Perry Township	165.54	266.41		I-70 – Wheeling, Columbus	Exit 164 on I-70
		New Concord	170.74	274.78		SR 83 to I-70
	Guernsey	Cambridge	177.18	285.14		SR 723 south to I-70	Northern terminus of SR 723
			179.23	288.44		SR 209 west (5th Street)	Western terminus of SR 209 concurrency
			179.51	288.89		SR 209 east (Southgate Parkway) to I-70	Eastern terminus of SR 209 concurrency
			179.84	289.42		US 40 east (Wheeling Avenue)	Eastern terminus of US 40 concurrency
		Cambridge Township	181.98	292.87		I-77 – Marietta, Cleveland	Exit 47 on I-77
Jefferson Township		188.31	303.06	Salt Fork State Park
Madison Township		191.11	307.56	SR 285 (Jefferson Road)
Antrim		194.96	313.76	SR 513 south to I-70	Northern terminus of SR 513
Londonderry Township		202.55	325.97	SR 800 south – Barnesville	Western terminus of SR 800 concurrency
Harrison	Freeport Township	203.16	326.95	SR 800 north – Freeport, Clendening Dam	Eastern terminus of SR 800 concurrency
	Piedmont	206.02	331.56	SR 331 east – Holloway	Western terminus of SR 331
	Cadiz Township	212.54	342.05	SR 519 east – New Athens	Western terminus of SR 519
	Cadiz	219.29	352.91	219	US 250 west – New Philadelphia	Western terminus of US 250 concurrency
		220.14	354.28	220	US 250 east / SR 9 – Scio, Cadiz, Bridgeport	Eastern terminus of US 250 concurrency
	Green Township	224.53	361.35	224	SR 151 west – Jewett, Scio	Western terminus of SR 151 concurrency
	Hopedale	226.27	364.15	226	SR 151 east – Hopedale, Smithfield	Eastern terminus of SR 151 concurrency
	Green Township	227.87	366.72	-	Township Road 65	Western terminus of freeway section
Jefferson	Bloomingdale	231.37	372.35	231	SR 152 – Bloomingdale, Fairgrounds
	Wayne Township	233.78	376.23	233	Reeds Mills, Broadacre	Access via CR 22A
	Reeds Mill	235.21– 235.25	378.53– 378.60	235	CR 22A – Wintersville, Reeds Mills	Eastbound exit and westbound entrance
	Wintersville	237.48	382.19	237	SR 43 – Carrollton, Wintersville
	​	240.18	386.53	240	Lovers Lane – Steubenville
	​	241.81	389.16	241	John Scott Highway – Steubenville	Serves Eastern Gateway Community College
	Alikanna	242.90	390.91	242	SR 7 north / SR 213 north – East Liverpool	Western terminus of SR 7 concurrency; southern terminus of SR 213 (not signed westbound)
	Steubenville	243.81	392.37	244A	SR 7 south – Downtown	Eastern terminus of SR 7 concurrency; signed as exit 244 westbound
		244.20	393.00	244B	University Boulevard	Westbuond exit is via exit 244A; serves Franciscan University of Steubenville
Ohio River			244.32 0.0	393.19 0.0	Veterans Memorial Bridge
West Virginia	Brooke	​	0.6	0.97	1	WV 2 south – Follansbee, Wheeling	Western terminus of WV 2 concurrency
		​	1.2	1.9	2	WV 2 north (Main Street) – Downtown Weirton	Eastern terminus of WV 2 concurrency
	Hancock	No major junctions
	Brooke	Weirton	3.2	5.1	3	CR 507 (Harmon Creek Road) / CR 1 (Cove Road)
			4.3	6.9	4	CR 13 (Three Springs Drive) – Weirton	No CR 13 signage eastbound; serves West Virginia Northern Community College
	Brooke–Hancock county line		5.5	8.9	5	WV 105 (Colliers Way)
	Hancock		6.0	9.7	—	US 22 east – Pittsburgh	Continuation into Pennsylvania
1.000 mi = 1.609 km; 1.000 km = 0.621 mi       Concurrency terminus       Incomplete access

• Special routes of U.S. Route 22

• Speed Limits for Route 22 in New Jersey
• Endpoints of U.S. Highway 22