The state route begins at a T-intersection with SR 134 in Buford, an unincorporated community within Clay Township.

SR 321 heads southeast through Clay and White Oak Township through a mix of single-family homes and farmland.

The route exits the village and crosses the White Oak Creek before curving to the northeast through more farmland.

The road ends at a skewed T-intersection with US 62 on the border of White Oak and Concord Townships.

[3] The first part of SR 321 brought into the state highway system was a gravel-paved spur from US 62 to Mowrystown circa 1932.