Its southern/western terminus is in Round Rock, Texas, at an interchange with Interstate 35, ten miles (16 km) north of Austin.

The highway then travels due east to Carthage, where it meets US 59 (Future I-369), before resuming a northeasterly direction and crossing into Louisiana near Panola.

In Homer, the route resumes a more northerly direction, traveling through Haynesville before crossing the Arkansas border about 7 miles (11 km) south of Emerson.

East of Kingsland, the highway travels in a more northerly direction as it prepares to enter the Pine Bluff metropolitan area.

US 79 continues to the east and northeast, through Marianna and Hughes, before turning due north to an intersection with Interstate 40 near Jennette.

US 79 enters Memphis with US 70, US 64 and Tennessee State Route 1, travelling east along E.H. Crump Boulevard, turns north on Third Street and travels through Downtown Memphis along both Second and Third Streets (3rd St is three lanes of northbound traffic and 2nd St is three lanes southbound).

US 70A splits off from US 79 near Atwood and US 79 continues to the northeast into Henry County, passing through the city of Paris, then crosses the Tennessee River.

Once US 79 enters Stewart County, it passes to the south of the Land Between the Lakes recreation area and crosses the Cumberland River.

This section of US 79 in Clarksville was previously called the Guthrie Highway, for nearby Guthrie, Kentucky, but in 1994, the name was changed to honor Wilma Rudolph, an Olympic runner from Clarksville, who won three gold medals in the 1960 Rome Summer Olympic Games.

US 79 enters Kentucky from Tennessee in Todd County west of Guthrie and runs northeast into Logan County, now terminating at the junction of US 68 on the east side of Russellville on its bypass around the south side, 26.8 miles (43.1 km) from the Tennessee state line, after formerly terminating at a junction with US 431 in Russellville.