Several segments of U.S. 281 are concurrent with Interstate routes, including I-69C in the Rio Grande Valley, I-37 in San Antonio, and I-44 north of Wichita Falls.

[1][2] The western segment, officially listed as a spur connection by TxDOT and often labeled on maps as US 281 Spur, begins just north of the McAllen–Hidalgo–Reynosa International Bridge in Hidalgo and travels north along International Boulevard before turning east onto Coma Avenue and entering Pharr.

[1][3] The two segments (along with Spur 600, which provides access to the Pharr–Reynosa International Bridge) meet at Cage Boulevard, where signage changes to south–north, and the highway turns to the north.

[5] US 281 travels through small towns and sparsely-populated areas, alternating between a divided highway and a main street and passing through a Border Patrol checkpoint south of Falfurrias,[6] until joining I-37 north of Three Rivers.

In Central Texas, it serves as the main street of Blanco before beginning a concurrency with US 290 south of Johnson City.

The reason for this initial lack of direct interchange was due to litigation filed in the late 1960s against the Texas Highway Department over the highway's original construction alignment through portions of Brackenridge Park and Olmos Park that were alleged to be in violation of several Federal laws, ultimately including NEPA.

As a result of the Supreme Court decision[9] in a more advanced and very similar case involving the proposed construction of I-40 through Overton Park in Memphis, Tennessee which upheld and affirmed the plaintiffs in that circumstance and precluded that highway's construction through the parkland with Federal funding, the Texas Highway Department chose instead to construct the McAlister Freeway entirely with State funding using a modified design that would increase curvature but limit encroachment into and noise impact on the Sunken Gardens area within Brackenridge Park.

Funding of various highway projects from around Texas was re-allocated to the McAlister Freeway project, which was initially completed with only the indirect interchange via existing surface streets to Loop 410 since it required no Federal funding or approval and the Loop 410 overpass of that location where the McAlister Freeway main lanes would pass beneath had already been completed many years earlier.

[12] After nearly two decades of planning an delays, TxDOT upgraded this section of highway from a superstreet to a limited–access freeway, with construction beginning in 2017 and concluding in 2022.

The highway travels for 0.2 miles (0.32 km) east along E. E. Ohnmeiss Drive before reaching an intersection with US 183 (Key Avenue) / US 190 (Central Texas Expressway).

After running for 0.4 miles (0.64 km) along Key Avenue, the highways then intersect the main route of US 281, which is the northern terminus of Truck US 281.