State Route 378 (SR 378, OH 378) is a north–south state highway in the south-central portion of Ohio. State Route 378's southern terminus is at State Route 243 about 5 miles (8.0 km) south of the unincorporated community of Willow Wood. Its northern terminus is at State Route 141 nearly 4 miles (6.4 km) northwest of Willow Wood.

Created in the mid-1930s, and existing entirely in Lawrence County, State Route 378 parallels Symmes Creek for its entire length. A part of the northern segment of the state highway runs through a small section of Wayne National Forest.

All of State Route 378 is located within Lawrence County. The highway is inclusded as a part of the National Highway System, a system of highways deemed most important for the country's economy, mobility and defense.

When it made its debut in 1935, State Route 378 existed just in the form of its current northern 4 miles (6.4 km) segment between State Route 217 and State Route 141. Two years later, State Route 378 would take on its current look when it was extended via a short concurrency with State Route 217 heading east, then onto its current southern stretch to a junction with State Route 243. Since that extension, there have been no other significant changes to the routing of State Route 378.

The entire route is in Lawrence County.