The highway serves the small communities of Whitsett and Campbellton, about 45 miles (72 km) southeast of San Antonio in the state of Texas.

[2] The highway enters the town and crosses FM 99 before leaving.

[2] Just north of Whitsett, the highway turns from a northwesterly direction to a more northward one.

US 281 is concurrent with FM 791 through the town before separating just north of the city limits.

US 281 reaches its northern terminus at another interchange with I-37/US 281 about 2+1⁄2 miles (4.0 km) north of Campbellton.