State Highway 21 runs from the Texas-Louisiana boundary east of San Augustine to San Marcos in east and central Texas. SH 21 mostly follows the alignment of the Old San Antonio Road and the El Camino Real, except for the portion between Midway and Bryan, where the Old San Antonio Road took a more northerly route, and SH 21 follows a more direct route. That section of the Old San Antonio Road is served by Texas State Highway OSR.

The Old San Antonio Road was a historic roadway located in the U.S. states of Texas and Louisiana. Parts of it were based on traditional Native American trails. Its Texas terminus was about 35 miles (56 km) southeast of Eagle Pass at the Rio Grande in Maverick County, and its northern terminus was at Natchitoches, Louisiana. The road continued from Texas through Monclova to Mexico City.