The highway ends at an interchange in southern Elkhart after serving the northeastern region of Indiana.

US 33 enters Indiana from Ohio heading northwest towards Decatur, as a rural two-lane highway, passing through farmland with a few houses.

The road begins a concurrency with US 27, heading due north as a four-lane highway with a center turn lane.

The three routes head north having an intersection at the northern end of the US 224 concurrency, US 224 turns due west.

After the concurrency with US 224, US 27 and US 33 head north and then northwest towards Fort Wayne and the road becomes a four-lane divided highway.

West of the airport is the terminus of I-469, both US 24 and US 33 turns north onto I-69, passing through rural areas with farmland as a four-lane interstate.

North of the Airport Expressway interchange, the roadway becomes a six-lane interstate, passing through urban areas with a mix of commercial and industrial properties.

[2][3][4] The roadway leaves Fort Wayne heading northwest as a two-lane mainly rural highway, passing through farmland with some woods.

Both US 6 and US 33 head west away from Ligonier as a two-lane highway passing through farmland with some houses, for 5.75 miles (9.25 km).

[2][3][4] The road enters Goshen on the southeast side of the city as a two-lane highway with a center turn lane, passing commercial properties.

After the high school the road has a traffic light with the old alignment of US 33, before curving northwest and parallel to the Norfolk Southern Chicago Line.

The route leaves downtown Goshen as a four-lane undivided highway, passing through a commercial district and residential area.

The route heads towards Elkhart, paralleling the Norfolk Southern railroad and passing through Midway and Dunlap.

[2][3][4] The entire length of US 33 in Indiana is included as a part of the National Highway System (NHS).

[9][10] In the early 1920s, the Lincoln Highway was moved farther south between Valparaiso and Fort Wayne, to what is now known mostly as Old US 30, passing through Plymouth and Warsaw.

North of that intersection, US 33 departed to the northwest on Lima Road, before turning west on Coliseum Boulevard.