Although it travels from northwest to southeast, it is marked as a north–south highway.

From there, it travels northwest into the city limits of Decatur but largely goes around downtown using 22nd Street and Pershing Road.

On the northwest side of Decatur, IL 121 intersects with the concurrent I-72 and US 51.

IL 121 continues further northwest into Lincoln, where it has a concurrency with IL 10 through Lincoln as Keokuk Street and Woodlawn Road before terminating at I-55 just south of I-155.

When US 36 was established in the late 1920s, IL 121 was dropped east of Decatur.