State Route 251 (SR 251, OH 251) is a north–south state highway located in the southwestern portion of the U.S. state of Ohio. Its southern terminus is at U.S. Route 50 about 1 mile (1.6 km) south of St. Martin in northern Brown County. The northern terminus of State Route 251 is at U.S. Route 68 nearly 2.50 miles (4.02 km) northwest of St. Martin in southwestern Clinton County.

The path of State Route 251 takes it through northern Brown County and southwestern Clinton County. State Route 251 is not included as a component of the National Highway System, a network of highways identified as among the most important for the country's economy, mobility and defense.

When it debuted in 1925, State Route 251 was routed along what is now U.S. Route 68 between U.S. Route 50 in Fayetteville and the current northern terminus of State Route 251 south of St. Martin. U.S. Route 68's predecessor, State Route 53, duplexed with U.S. Route 50 east to the current southern terminus of State Route 251, and then followed the entire present alignment of State Route 251 before resuming its northward path along the current alignment of U.S. Route 68. In 1930, State Route 251 and State Route 53 swapped alignments, such that State Route 53 now followed a straight alignment north out of Fayetteville that U.S. Route 68 utilizes today, and State Route 251 now appeared along its present-day routing.