After departing 641 a mile south of the Interstate, 46 becomes a heavily traveled modernized 2-lane highway through Spencer where it intersects SR 67 and US 231.

It then goes by the College Mall in Bloomington where it makes a left turn and winds towards the artist colony of Nashville passing by SR 446 and Lake Monroe.

At this point it makes a right turn and becomes a minor 2-lane highway as it closely follows I-74 until its eastern terminus at US 52 in northeastern Dearborn County.

In 1974, the portion of the route west of Columbus to the Brown County Line was named Jonathan Moore Pike, after a settler in the area who served in the Revolutionary War as a member of the Commander-in-Chief's Guard.

However, a major construction project completed in November 2012 widened the road to 4 lanes and alleviated the issue on this part of the roadway.