In the U.S. state of Indiana, Interstate 74 traverses central parts of the state from west to east. It connects Champaign in Illinois with Indianapolis in the center of the state, and Indianapolis with Cincinnati in Ohio. Interstate 74 covers 171.54 mi in the state of Indiana.

The Indiana portion of Interstate 74 begins on the Illinois border near Danville, Illinois and travels due east. Shortly into Indiana, the interstate crosses the Wabash River near Covington. I-74 continues east where it passes over US 136 and intersects US 41 at Veedersburg about 15 miles east of the Illinois border. 19 miles later, the interstate intersects US 231 providing access to Crawfordsville to the south. I-74 runs nearly parallel to US 136 from the Illinois border until US 136 terminates at Interstate 465.

Once I-74 reaches Indianapolis it continues south, overlapping I-465. I-74 runs concurrent with I-465 on I-465's western and southern segments. It also overlaps with US 31, US 36, US 40, US 52, and several state highways, for varying lengths of its route around Indianapolis. I-74 also crosses the White River and passes by the Indianapolis International Airport on the southwest side of Indianapolis. Once I-74 reaches the southeast side of Indianapolis it diverges from I-465 and continues to the southeast. At this intersection, I-74 picks up US 421 from where it will run concurrent.

Outside of the Indianapolis area, I-74 continues southeast and runs past Shelbyville. Near the halfway point between Indianapolis and the Ohio border, I-74 runs through Greensburg. US-421 diverges and runs south through Greensburg. Continuing on east, I-74 runs parallel to State Route 46. Just west of the Ohio border, I-74 crosses the Whitewater River. It also intersects with and begins to overlap with US 52. The two then continue and cross into Ohio at Harrison.