North of Greensburg, US 421 intersects and merges with I-74 west, through the Shelbyville area en route to Indianapolis.

Originally, US 421 followed Michigan Road into Indianapolis, which turns into Southeastern Avenue and heads to downtown.

Originally, the highway's end was a few miles north at the junction with US 12 near the shores of Lake Michigan.

After crossing the Ohio River US 421 has a short concurrency with State Road 56 (SR 56).

US 421 heads towards Versailles, passing through an intersection with State Road 250 (SR 250).

US 421/SR 39 heads northwest towards Delphi passing through an intersection with State Road 26 (SR 26).

After the concurrency with US 24, US 421 runs into mostly rural areas as it leaves White County and enters Pulaski County, turning from a northwest trajectory to a due north one.

It enters the tiny town of Francesville where it shares a couple of junctions and concurrencies.

Just before leaving Pulaski County, US 421 crosses into the unincorporated community of Radioville.

US 421 heads north towards Michigan City, passing through Monon, Wanatah, and Westville.

US 421 from Reynolds to Michigan City was originally State Road 43 (SR 43).