When US 380 was commissioned in 1932, it took over the entire former route of U.S. Route 566, an original 1926 route. The entire route of US 566 was within the state of New Mexico, from an intersection with US 366 (modern-day US 70) east of Ruidoso to US 85 in Socorro, New Mexico. US 566 never intersected with its nominal parent, U.S. Route 66.
At Graham, US 380 takes a sharp turn toward the north, passing just north of Lake Eddleman and Lake Graham before turning back to the west toward the town of Newcastle, where it makes a brief turn due south, and then back west again at a junction with Texas State Highway 61 maintaining a generally due-westerly heading all the way through the communities of Throckmorton, Haskell and Rule. After Rule, US 380 takes a turn to the southwest and passes through the tiny community of Old Glory before making another abrupt turn back toward the north to the town of Aspermont, where it briefly shares a route with US 83 before breaking off again in a northwesterly bearing toward the community of Swenson.
From Swenson, US 380 passes thorugh several thousand acres of private ranch land throughout rural Stonewall and Kent Counties before coming to an intersection with Texas State Highway 70 just south of Jayton where it takes another sharp turn to the southwest. It follows this southwesterly bearing for approximately 6.5 miles, where TX 70 leaves the route and continues on to the southeast, and US 380 resumes its near due-westerly heading all the way to the ghost town of Clairemont. After Clairemont, the highway winds its way through the rest of rural Kent and Garza Counties before coming to an intersection with US 84 in downtown Post.
West of Post, US 380 again maintains an almost due-westerly bearing and passes through the towns of Tahoka and Brownfield, where it meets up with US 82. After passing through Brownfield, US 380/82 treks west through the ghost towns of Gomez and Tokio and on into Plains, where US 82 leaves the route with a turn toward the southwest and US 380 veers off to the northwest. After approximately 3 miles, the highway once again turns due-west, where it passes through the tiny community of Bronco and passes into New Mexico at an intersection with New Mexico State Highway 769.