It intersected with its parent, U.S. Route 80, at Cisco until 1971, when it was rerouted along the former SH 24 from that highway's western terminus near Old Glory to Greenville.

US 380 passes through some of the far northern suburbs of the Dallas/Fort Worth Metroplex, including (from west to east) Denton, Frisco, McKinney and Princeton.

US 380 enters Texas at a crossing with Farm to Market Road 769, travelling generally due east before meeting up with US Route 82 in Plains.

The route continues due east through Texas South Plains farmland, passing through Tahoka, before falling off the Llano Estacado and reaching Post.

The highway then meanders east through rural Garza and Kent Counties before reaching the ghost town of Clairemont.

The road then travels through several thousand acres of private ranchland in Kent and Stonewall Counties before reaching Swenson.

US 380 continues to the east and northeast through Bryson before reaching an intersection with US Route 281 and Texas State Highway 114 in Jacksboro.

The route then continues east, passing through Princeton before crossing the northern fringe of Lake Lavon, and reaching Farmersville, where it is signed as the Audie Murphy Parkway.

US 380 east of Denton, and west of McKinney,[2] has had numerous fatal vehicle accidents, per public statements by law enforcement and fire department officials.