Existing entirely within Medina County, SR 421's endpoints are at opposite ends of the concurrency of U.S. Route 42 (US 42) and US 224, which together form the four-lane bypass of Lodi.

SR 421 begins at a four-ramp parclo interchange in Harrisville Township that also doubles as the western split of the concurrency of US 42 and US 224.

The first mile (1.6 km) of SR 421 is predominantly rural, amid a mixed landscape of farmland and woods.

In this stretch, the state highway closely parallels the CSX railway that runs to the north of the route.

After passing some businesses, the highway meets Highland Drive at a flashing beacon intersection, then enters into a wooded area lined with a few homes upon departing Lodi and re-entering Harrisville Township.