As of 2004, the highway's eastern terminus is west of Joplin, Missouri at an intersection with Interstate 44, which it shares with U.S. Route 166. It originally ended in Garden City, Kansas; in 1996 it was extended to its current western terminus in Granada, Colorado at an intersection with U.S. Route 385.
US-400 and US-54 begin a long concurrency at Mullinville which passes through Greensburg, Pratt, and Kingman before entering Wichita. While in Wichita, US-400 and US-54 intersect Interstate 235 and the concurrency of US-81 and Interstate 135. K-96 provides a short freeway connection to Interstate 35, which is also the Kansas Turnpike. At Augusta, US-400 and US-54 enter into another concurrency with US-77, and US-400 breaks from this concurrency at Haverhill.
US-400 continues east through several small towns before turning southeast to go through the Fredonia area and intersecting US-75 at Neodesha. After a brief concurrency with US-75, it turns east, intersecting US-59 near Parsons before intersecting US-69 south of Pittsburg. It then turns south with US-69 and at Crestline, follows US-69A south to Riverton. US-400 then turns east with US-166 at Baxter Springs, and the two highways run concurrently eastward into Missouri.
U.S. Route 400 was created to run down a corridor for a possible extension of Interstate 66 which only runs from Washington, DC to northern Virginia. A call had been made to extend this interstate to California, but extension west of Wichita, Kansas has been cancelled due to lack of enthusiasm from the states traversed, expense, and the lack of any other road along that path. US 400 was supposed to be a temporary route until I-66 is built. The eastern terminus of US 400 at I-44 near Joplin, Missouri is where I-66 would leave its proposed concurrent section with that interstate to enter Kansas. It will be many years before such an interstate will be built, if at all.