U.S. Route 83 is one of the longest north–south U.S. Highways in the United States, at 1,885 miles (3,034 km). Only four other north–south routes are longer: U.S. Routes 1, 41, 59 and 87. The highway's northern terminus is north of Westhope, North Dakota, at the Canadian border, where it continues as Manitoba Highway 83. The southern terminus is in Brownsville, Texas, at the Veterans International Bridge on the Mexican border, connecting with Mexican Federal Highway 180.

Despite its length it has comparatively few concurrencies with any Interstate highways, and those segments are short. In no place has it been decommissioned as a route.

US-83 traverses the Oklahoma panhandle along the western border of Beaver County, but in this brief 37-mile (60 km) stretch it encounters no fewer than three other federal highways. Approximately ten miles from the Texas line, US-83 intersects US-412 in the hamlet of Bryan's Corner. Continuing its journey northward, the highway crosses the Beaver River, then intersects US-64 in Turpin. US-83 North and US-64 East are co-signed for three northbound miles, where US-64 turns eastward. At this intersection, US-270 West joins the highway, and together with US-83 proceeds northbound for the final six miles (10 km) to the Kansas line.

US 83 enters the Sunflower State in Seward County, approximately four miles south of Liberal, where it intersects US 54. North of Liberal, US 83 begins a multiplex with US 160, and the highways remain joined until reaching Sublette, the seat of Haskell County. US 83 and US 160 split north of Sublette, with US 160 heading west toward Ulysses, and US 83 continuing north toward Garden City.

At Garden City, US 50 and US 400 join US 83 for a brief concurrency on a bypass around the east and north sides of the city while U.S. 83 Business follows the former routing through downtown. All three routes cross K-156, also known as Kansas Avenue, in the northwest portion of the city. At the north end of the US 50-83 Business route, US 83 splits and heads north toward Scott City, while US 50 and US 400 remain joined through the rest of the state. The highway passes through largely unpopulated areas of Finney County and Scott County before reaching a junction with K-96 in downtown Scott City.

In northern Scott County, K-4 has its origins at US 83, heading east toward Healy, and US 83 traverses through rolling farmlands until reaching Oakley, the seat of Logan County. US 83 reaches US 40 less than a mile west of Interstate 70, and the two highways jog west for a brief multiplex before US 83 splits and crosses I-70.

North of I-70, US 83 begins a concurrency with K-383, formerly US 383. Passing to the east of Gem in Thomas County, US 83/K-383 takes a sharp northeasterly track through Rexford and Selden. After passing through Selden, K-383 splits from US 83 and continues northeast to US 36, while US 83 meets the beginning of K-23.

US 83 returns to a northerly course at the Sheridan County–Decatur County line, and passes through Oberlin at US 36. Oberlin is the last area of significant population the highway passes in Kansas; the next city is McCook, Nebraska.

U.S. 83 enters Nebraska south of McCook, where it meets U.S. Route 6 and U.S. Route 34. It continues northward to North Platte, where it intersects Interstate 80 and U.S. Route 30. After leaving North Platte in a northeasterly direction, it turns north near Thedford and goes north through the Sand Hills to Valentine. For 5 miles (8.0 km) before Valentine, it runs concurrent with U.S. Route 20. After passing through Valentine, it continues north to enter South Dakota.

U.S. 83 enters South Dakota south of Olsonville on a segment of highway which passes through the Rosebud Indian Reservation. After a brief overlap with U.S. Route 18 in Mission, the route turns north and meets Interstate 90 at Murdo. The two routes overlap as U.S. 83 goes east with I-90 until Vivian, where U.S. 83 turns north. At Fort Pierre, U.S. 83 meets U.S. Route 14 and South Dakota Highway 34. The three highways overlap as they cross the Missouri River and enter Pierre. At Pierre, SD 34 separates and U.S. 83 turns northeast with U.S. 14. They separate near Blunt and U.S. 83 turns northward. U.S. 83 briefly overlaps with U.S. Route 212 near Gettysburg and with U.S. Route 12 through the Selby area. U.S. 83 leaves South Dakota north of Herreid.

The South Dakota section of U.S. 83, with the exception of concurrencies with U.S. 18, Interstate 90, U.S. 14, U.S. 212, and U.S. 12, is defined at South Dakota Codified Laws § 31-4-180.

U.S. 83 enters North Dakota at the South Dakota state line, near the town of Hague, and runs northward for approximately 68 miles (109 km), serving the small cities of Strasburg and Linton before reaching Interstate 94. It follows I-94 west to Bismarck, where it resumes a generally northward course as a four lane highway.

Headed toward Minot U.S. 83 traverses mostly agricultural land, passing through the some small cities such as Wilton, Washburn and Underwood north to Max. Leaving Underwood, U.S. 83 encounters a large strip-mining coal (lignite) operation which can, not only be seen from the roadway in the vicinity of Falkirk, but a small viaduct carries coal mining cars over the highway. North of Coleharbor, U.S. 83 briefly merges both roadways and shares land with an adjacent railroad line in order to cross a viaduct that separates Lake Sakakawea from Lake Audubon. North of the lakes, the surroundings return to cropland and grazing land though a wind farm is located south of Minot.

U.S. 83 passes directly through Minot, where it is known as Broadway, although a bypass to the west of town is an alternative route. From Minot, the northbound route passes Minot Air Force Base where it returns to a two-lane highway, and shares a roadway with eastbound North Dakota Highway 5 about 30 miles (48 km) north of the base for about 10 miles. The highway then diverges from N.D. 5 to head north to the Canadian border.