From Littlefield, US 385 continues northward until it crosses Interstate 40 and then goes in a half circle to Hartley, where US 385 joins U.S. Highway 87.

US 385 and US 87 follow a northwest track until the two meet U.S. Highway 54 then split, with US 385 continuing northward until it exits Texas at the Oklahoma border.

The three highways run northeast into the county seat, Boise City.

In the middle of town, the highways come to a traffic circle surrounding the Cimarron County Courthouse.

At Custer, it begins an overlap with U.S. Route 16, which ends near Hill City.

U.S. 385 gradually turns in a northwesterly direction and ends at an intersection with U.S. Route 85 at Deadwood.

[4][5] Originally, the route continued along US 287 north of Lamar, Colorado, splitting in Kit Carson to follow US 40 east to meet up with the present-day alignment in Cheyenne Wells.

[5] In South Dakota, in 2009, the South Dakota Department of Transportation designated US 16/US 385 between Custer and Hill City, which passes by the Crazy Horse Memorial, now being carved in the Black Hills.