Situated entirely in the southern portion of Brown County, the southern terminus of State Route 221 is at U.S. Route 52 in the eastern end of Higginsport, a village set along the banks of the Ohio River.

The northern terminus of State Route 221 is at State Route 125 in the western portion of Georgetown, the county seat of Brown County.

The entirety of State Route 221 is situated in the southwestern quadrant of Brown County.

State Route 221 is included as a part of the National Highway System.

At the time, it followed the routing of what is now the county-maintained Old U.S. 68 running between Ripley and Georgetown.