U.S. Highway 181 is a south–north U.S. Highway located entirely in the state of Texas. Both termini are at Interstate 37, the road that it mainly parallels to the east. US 181 begins in Corpus Christi, Texas at mile marker 0 to the south, through south-central Texas to just south of San Antonio to the north (mile marker 131), for a total length of 137 miles (220 km).

The highway's northern terminus is at an intersection with Interstate 37 one mile (1.6 km) south of San Antonio's Interstate 410 loop, about 12 miles (19 km) northwest of Floresville. Prior to the Interstate era, US 181 traveled into Downtown San Antonio along Presa St. to an intersection with its parent route, US 81, which then ran along Alamo St.

Its southern terminus is in Corpus Christi, Texas at Interstate 37 near the Gulf of Mexico. I-37 and US 181 have mutual termini, such that traffic traveling southbound on I-37 will automatically merge onto northbound US 181, and vice versa.

Proceeding northbound, US 181 runs through the following Texas counties: Nueces, San Patricio, Bee, Karnes, Wilson, and Bexar. At its southern terminus with Interstate 37 in Corpus Christi, TX, US 181 traverses as a freeway in the northeast direction across Harbor Bridge and the Nueces Bay Causeway, before entering Portland, TX. Past the Nueces Bay Causeway through Portland, US 181 shares a duplex with Texas State Highway 35.

Immediately after Portland is Gregory, where US 181 and TX 35 splits, and the freeway portion of US 181 ends. SH 35 proceeds eastbound to Aransas Pass and Rockport while US 181 proceeds northwest towards Taft and Sinton. US 181 shares a duplex with SH 188 and US 77 Business in Sinton, and makes a right turn at San Patricio Street, proceeding northbound.

North of Sinton, US 181 passes through the towns of St. Paul, Papalote, and Skidmore, before reaching Beeville. US 181 business runs through downtown Beeville while drivers passing by can use the US 181 freeway bypass on the east side of town. In Beeville, US 181 intersects with US 59 (Future I-69W) (northbound to Victoria/Houston & southbound to Laredo).

North of Beeville US 181 passes through a number of unincorporated towns including Normanna, Pettus, and Tuleta before reaching Kenedy. US 181 business serves downtown while US 181 runs on the west side of town. Immediately north of Kenedy is Karnes City, where US 181 business runs parallel again east of US 181 through Karnes City.

North of Karnes City US 181 passes through Hobson (unincorporated), followed by Falls City, Poth, and Floresville. US 181 business runs west of US 181 through downtown Floresville.

North of Floresville US 181 passes through the town limits of Elmendorf before intersection with State Loop 1604 (Anderson Loop, surrounding San Antonio), and ends 8 miles north at its northern terminus at I-37, just south of I-37 and I-410 on San Antonio's far south side.

US 181 is one of the original routes accepted by AASHO (now-AASHTO) in November 1926. Its original northern terminus was at a junction with its parent, US 81, and US 90 in Downtown San Antonio. By 1968, the portion between Downtown and Loop 13 had been removed from the state highway system. The completion of I-37 in San Antonio during the 1970s resulted in the truncation of US 181 to its interchange with that freeway, although the AASHTO route log in 1989 stated that US 181 extended northward along I-37 to a common northern terminus at I-35/US 281. The segment north of this point along Presa Street was transferred to Spur 122.

In 2003, TXDOT began planning to replace the existing Corpus Christi Harbor Bridge due to maintenance and safety issues as well as to provide long term access to the Port of Corpus Christi to larger ship vessels (including Panamax). Construction has begun to replace the bridge with the New Harbor Bridge, which will be a cable-stayed bridge compared to the current through arch bridge. The alignment of the new bridge. which is west of the old bridge, would begin at the northern terminus of SH 286 (exit 1C on I-37) and cross the Corpus Christi Ship Channel before merging with the current US 181 alignment. Once completed, the Corpus Christi Harbor Bridge will be demolished, and US 181 will be rerouted onto the new bridge. Groundbreaking on construction took place on August 8, 2016 and was scheduled to be completed by the spring of 2020, but was extensively delayed due to engineering and design issues, and is tentatively planned to be completed in 2025.

County	Location	mi	km	Destinations	Notes
Nueces	Corpus Christi			I-37 to SH 286 / Shoreline Boulevard / Broadway Street / Spur 544 – Bayfront, Corpus Christi Museum, Airport, San Antonio, Chapman Ranch, Robstown	south end of freeway; south end of SH 35 concurrency
				Tancahua Street / Staples Street	Southbound exit and northbound entrance
				Port Area	Southbound exit and northbound entrance
				Corpus Christi Harbor Bridge over Corpus Christi Channel
				Burleson Street - Corpus Christi Beach
				Beach Avenue - Corpus Christi Beach
Nueces Bay				Nueces Bay Causeway
San Patricio	Portland			Indian Point Park
				Frontage Road	southbound access only
				FM 893 (Moore Avenue) – Taft	no direct southbound exit (signed at FM 2986)
				FM 2986 (Wildcat Drive) – Sinton
				Lang Road	southbound exit only
				FM 3239 (Buddy Ganem Drive) to Northshore Boulevard / FM 2986
	​			La Quinta Terminal	northbound access only
	Gregory			SH 35 north to SH 361 south – Aransas Pass, Rockport, Houston, Port Aransas	interchange; north end of freeway; northbound exit and southbound entrance; north end of SH 35 concurrency
				FM 3284 north – Woodsboro
	​			To SH 361 south / SH 35 north (via Spur 202 / FM 2986) – Ingleside, Port Aransas, Aransas Pass, Houston	interchange
	Taft			FM 631 east	South end of FM 631 concurrency
				FM 631 west (Davis Road) – Odem	South end of FM 631 concurrency
	​			FM 1074 south
	Sinton			SH 89 north / SH 188 east to Future I-69E / US 77 – Rockport, Refugio, Beeville	Interchange; south end of SH 188 concurrency
				FM 2046 south (Sodville Avenue)
				Bus. US 77 north (Vineyard Avenue) – Calallen, Corpus Christi	South end of US 77 Bus. concurrency
				Bus. US 77 south (San Patricio Street) / SH 188 west (Sinton Street) – Mathis, Victoria	North end of US 77 Bus. and SH 188 concurrencies
				Future I-69E / US 77 – Corpus Christi, Calallen, Victoria, Refugio	interchange; U.S. 77 is the future Interstate 69E
				SH 89 south – Refugio, Rockport, Gregory	interchange
	St. Paul			FM 3089 west
Bee	Skidmore			SH 359 west to I-37 – Mathis, Alice, Lake Corpus Christi State Recreational Area
				FM 797 west (Main Street)
	​			Bus. US 181 north – Kenedy	interchange; south end of freeway
	​			Emily Drive south	northbound exit only
	​			SH 202 – Refugio, George West
	Beeville			Future I-69W / US 59 – Laredo, George West, Victoria, Goliad	U.S. 59 is the future Interstate 69W
	​			FM 351 south – George West, Sinton
	​			FM 3355 (Charco Road)	interchange; north end of freeway
	​			Bus. US 181 south – Sinton
	Tuleta			FM 1465 west to FM 623 – Mineral
	Pettus			FM 623 – Mineral
	Tulsita			FM 798 west – Pawnee
Karnes	​			FM 743 north to FM 623 west / FM 1348 west – Kenedy, Pettus
	Green			FM 2509 north – Kenedy
	​			FM 632 east (Allen B. Polunsky Drive) – TDCJ Connally Unit
	​			Bus. US 181 north to FM 2509 – Karnes City, Pettus
	Kenedy			FM 1145 / SH 72 Truck east – truck route to SH 239 east / FM 792, Three Rivers, Goliad, Cuero	south end of SH 72 Truck overlap
				SH 72 / SH 239 east – Three Rivers, Goliad, Cuero	north end of SH 72 Truck overlap
				FM 719 east to FM 792 – Helena
				Bus. US 181 south – Pettus
	Karnes City			SH 80 north / SH 123 north (US 181 Bus. north) – Seguin, Floresville, San Marcos, Luling
				FM 1353
				FM 99 – Coy City, Peggy, Whitsett
				Bus. US 181 south / FM 1144 west – Floresville, Peggy
	Hobson			FM 81 east – Panna Maria, Runge	South end of FM 81 concurrency
				FM 81 west	North end of FM 81 concurrency
	Falls City			FM 791 west (West Maverick Street) – Campbellton
				FM 887 west to FM 791 – Campbellton	South end of FM 887 concurrency
				FM 887 east – Pawelekville, Gillett	North end of FM 887 concurrency
Wilson	Poth			FM 541 to I-37 – McCoy, Kosciusko
				FM 427 north to FM 537 – Stockdale
	​			FM 537 east – Stockdale
	​			Loop 181 north (Sgt. Hugo Lange Loop) – Floresville Business District, Pleasanton, San Antonio
	Floresville			SH 97 west (Hospital Boulevard) to US 281 – Pleasanton, Jourdanton	South end of SH 97 concurrency
				SH 97 east / FM 536 west (Standish Street) to US 281 – Stockdale, Espey	North end of SH 97 concurrency
	​			Loop 181 south (Sgt. Hugo Lange Loop) – Floresville Business District, Pleasanton, Karnes City
	Calaveras			FM 775 – La Vernia
Bexar	​			Loop 1604 (Anderson Loop) – Elmendorf, Converse	interchange
	​			CPS Energy Calaveras Power Station	interchange
	San Antonio			Spur 122 north (South Presa Street)
				I-37 north – San Antonio	I-37 exit 132
1.000 mi = 1.609 km; 1.000 km = 0.621 mi       Concurrency terminus

US 181 has business routes in Beeville, Kenedy, and Karnes City. The routes are previous alignments of US 181 through these cities, and were previously designated in the state highway system with other route numbers. The designations were changed to Business US 181 by TxDOT in 1991. A de facto fourth route, along a former alignment through Floresville, is designated Loop 181.

Business US 181 in Beeville travels through central Beeville while mainline US 181 uses a freeway bypass to the east of the city. It is officially designated by TxDOT as Business US 181-J, and was designated as Loop 516 on May 31, 1973 (which was signed as a business route of US 181), but was changed to Business US 181-J on June 21, 1990.

Business US 181 in Kenedy travels through central Kenedy while mainline US 181 passes to the west of the city. It is officially inventoried by TxDOT as two separate routes, with a discontinuity at SH 72.

• The southern segment, from US 181 northward to SH 72, is designated as Business US 181-G, and was formerly Spur 259 from September 25, 1952 until June 21, 1990, but was signed as business US 181.

• The northern segment, from SH 72 northward to US 181, is designated as Business US 181-F, and was formerly Spur 258 from September 25, 1952 until June 21, 1990, but was signed as business US 181.

Although not officially concurrent with SH 72, the signage in the area directs traffic from one segment to the other, effectively completing the loop.

Business US 181 in Karnes City travels northward and then westward through central Karnes City while mainline US 181 skirts the southwestern edge of the city. It is officially inventoried by TxDOT as two separate routes, which connect at the intersection with SH 80 / SH 123 in the east side of the city.

• The southern segment, from US 181 northward to SH 80/123, is designated as Business US 181-E. The route was previously part of SH 80, but it still signed as SH 80/123 to facilitate access to SH 80/123 for traffic from northbound US 181.
• The northern segment, from SH 80/123 westward to US 181, is designated as Business US 181-D. The route was previously part of FM 1144.

US 181's former alignment in Floresville is inventoried as Loop 181 by TxDOT. The route was designated on October 15, 1946 when US 181 was realigned to the east. The route begins north of the city limits; within the city, it has a brief concurrency with FM 536 and intersects SH 97 before rejoining US 181 in the southeastern section of the city.

• U.S. Highway 81
• U.S. Highway 281
• Interstate 37

• Endpoints of US highway 181