State Highway 21, or SH 21, runs from the Texas-Louisiana boundary east of San Augustine to San Marcos in east and central Texas.

SH 21 was one of the original 26 routes proposed in Texas in 1917 along a route from St. Augustine to Gonzales. There was proposed extension southward to Karnes City by 1922, but most of it was transferred to SH 80 instead. In 1926, the terminus was shortened to Giddings. By 1943, the western terminus had been rerouted through Paige to end in San Marcos, along its current route.

SH 21 has one business route.

Business State Highway 21-H is a Business Loop that runs through Kurten in central Texas. The road was bypassed in 2002 by SH 21.