It enters the state south of Evansville as a four-lane divided highway passing around Vincennes and traveling north to Terre Haute.

It passes through Rockville, Veedersburg, and Attica before returning to a four-lane divided highway when SR 63 terminates in Warren County.

It remains a four-lane divided highway until Lake County, where it becomes a main road known as Indianapolis Boulevard.

In the middle of this bypass there is a three-level stack interchange with US 50 and US 150 eastbound, headed for Washington, Indiana; Cincinnati, Ohio; and Louisville, Kentucky.

[4] US 50 splits to the west in the city, heading for Lawrenceville, Illinois, and St. Louis, Missouri, while US 41 and US 150 continue north.

US 150 leaves the concurrency in the south end of the city, headed west towards Danville and Moline, Illinois, while US 41 continues north through Terre Haute.

It approaches an interchange with Interstate 70, then passes by Honey Creek Mall and Indiana State University.

Past Attica, US 41 turns northwest and rejoins the four-lane highway near Kramer at the northern terminus of SR 63.

Past SR 63, US 41 has an interchange with US 52 eastbound, which heads southeast towards Lafayette and Indianapolis as a four-lane divided rural highway.

US 52 westbound joins with US 41 heading north towards Kentland[4] In 2008, a wind farm was built next to the highway near Earl Park.