U.S. Federal Route 421 is a north-south highway in Marion and Hamilton Counties. This highway briefly passes through Hamilton County twice. Once between Boone and Marion County. Then again on the Interstate 465 loop near mile-post 31. Like the other numbered surface highways at Indianapolis, U.S. Rt. 421 by-passes the city on the Interstate 465 loop. This highway runs along the north and eastsides from Michigan Road to Interstate 74 on the southeast side of the city. U.S. Rt. 421 passes through the following town in Marion-Hamilton Counties. Indianapolis U.S. Rt. 421 is multi-plexed in Marion-Hamilton Counties. Interstate 465, at Indianapolis.