The southern terminus is a rural intersection with State Road 14 in Barkley Township at Lewiston, 10 miles (16 km) northeast of Rensselaer.

SR 49 heads north, passing through Wheatfield and Kouts.

Between Valparaiso and Chesterton, SR 49 has interchanges with U.S. Route 6 and Interstate 80/Interstate 90/Indiana Toll Road.

After 1926, SR 49 was a two-lane highway from Valparaiso to Chesterton, known as "Old State Road 49".

When the Valparaiso Bypass was completed the old route was decommissioned and turned over to the City of Valparaiso, the City of Chesterton, and Porter County.