U.S. Route 281 in Texas is a major north-south highway in the U.S. state of Texas. U.S. 281 runs from Brownsville, just north of the US-Mexico Border to the Texas-Oklahoma state line in Burkburnett north of Wichita Falls congruent with I-44.

US 281 begins at an intersection with Business US 77 and SH 48 about 2 miles (3.2 km) from the Mexico border. It travels along the border through the Rio Grande Valley, turning north at Pharr, travelling through many small towns, alternating as a divided highway and main street, until joining I-37. It splits with I-37 and travels through Pleasanton, travelling north to San Antonio. In San Antonio, US 281 overlaps I-410 on the south side of the city until the interchange with I-37. US 281 and I-37 then overlap north into Downtown San Antonio until I-37 ends at I-35. US 281 continues north from Downtown San Antonio as a freeway, intersecting I-410 again in Uptown San Antonio, with access to the San Antonio International Airport. A project to construct a stack interchange at I-410 (the "San Antonio Web") was completed June 9, 2008; formerly there was no direct access between the two freeways and surface streets were required travel between the freeways. North of San Antonio, US 281 is not a freeway and forms the Main Street of Blanco. It overlaps US 290 south of Johnson City. US 290 continues toward Austin, so US 281 and US 290 between San Antonio and Austin are available as a scenic and less congested alternate to I-35.

North of San Antonio, US 281 continues through central and north-central Texas, passing through many towns, including Stephenville, Mineral Wells and Jacksboro before reaching Wichita Falls, where the highway begins a concurrency with I-44 north across the Red River into Oklahoma.

U.S. Route 281 is a freeway three different times over its course in Texas, not counting overlaps with interstates. The first freeway portion is Cage Boulevard in the McAllen area that runs from US 83 north to Business US 281. The second time Hwy 281 becomes a freeway is in San Antonio. The freeway is known as the McAllister Freeway from its beginniing at the end of I-37 at an interchange with I-35. Just north of I-410, the freeway changes names to San Pedro Avenue, which used to be a surface street. The freeway ends just north of Loop 1604 at Sonterra Boulevard. From here, US 281 becomes a "super street." The highway has two interchanges in Bulverde. The third freeway runs on the east side of Wichita Falls. The highway then begins an overlap with US 287 that runs to I-44. The highway crosses the Red River into Oklahoma with I-44 and US 277.