US Route 421 in Indiana runs from Michigan City to Madison, following a route south-southeast through the Indianapolis area. From the northern terminus at US Route 20 in Michigan City, US Route 421 heads due south through rural areas. At the town of Reynolds, US Route 421 joins US Route 24 east to Monticello, and US Route 421 continues zigzagging south and east from there to Interstate 465 on the north side of Indianapolis. US Route 421 joins Interstate 465 east and south around Indianapolis, to then join Interstate 74 along another concurrency. At Greensburg, US Route 421 splits from Interstate 74 to cross the Ohio River at Madison into Kentucky.