Its southern terminus is at U.S. Route 50 (US 50) about one mile (1.6 km) south of St. Martin in northern Brown County.

The northern terminus of SR 251 is at US 68 nearly two and a half miles (4.0 km) northwest of St. Martin in southwestern Clinton County.

SR 251 is not included as a component of the National Highway System.

[4] When it was designated in 1925, SR 251 was routed along what is now US 68 between US 50 in Fayetteville and the current northern terminus of SR 251 south of St. Martin.

US 68's predecessor, SR 53, concurrent with US 50 east to the current southern terminus of SR 251, and then followed the entire present alignment of SR 251 before resuming its northward path along the current alignment of US 68.