[1] US 50 runs east–west across the southern portion of the state, between Interstate 70 (I-70) to the north and I-64 to the south.

After US 50 and I-255 leave Mehlvile and enter Columbia, they then run concurrently with Illinois Route 3 (IL 3), as well as the Great River Road, at a directional T interchange (exit 6).

At a trumpet interchange (exit 10), IL 3 and the Great River Road leave the freeway.

North of Trenton and Breese, each part of US 50 briefly becomes a four-lane divided highway with one diamond interchange each (one with IL 160 and one with Jamestown Road respectively).

East of Lawrenceville, US 50 becomes a four-lane divided highway for the rest of its run in the state.

[5] US 50 between Lebanon and Carlyle was moved to a northern alignment in October 1986 that bypassed several communities, including Trenton and Aviston.

Another modern bypass portion between O'Fallon and IL 127 shows evidence of a four-lane right of way as each bridge is paralleled by a second that remains unused and the graded roadbed for additional lanes is visible.