The total length of the southernmost segment of US 59 that passes through Texas and terminates at the Mexico–US border is 615 miles (990 km).

The US 96 designation was originally applied in 1926 from Rosenberg, Texas, near Houston, to Pharr in the Rio Grande valley.

[3] US 59 begins at the Mexican border with Loop 20 on the World Trade International Bridge over the Rio Grande in Laredo.

At under two miles (3.2 km), the two highways run together concurrently with I-69W from the Mexican border until I-35 in Laredo, where I-69W temporarily ends.

US 59 and Loop 20 continue to run together until just south of Lake Casa Blanca, where Loop 20 heads south to Mangana-Hein Road (and potentially into Mexico) and US 59 heads towards Freer; traveling in a mostly northeast direction.

From Freer, US 59 passes through the southeastern part of McMullen County, but does not intersect any highways.

Between Houston and Victoria, US 59 passes through Edna, Ganado, El Campo, and Wharton.

US 59 intersects many major Texas highways in Houston, including I-10 (which goes to San Antonio and Beaumont) and I-45 (which goes to Dallas and Galveston).

Leaving Houston, US 59 intersects Beltway 8 again on the northside of town, passing by Bush Intercontinental Airport and heads into Humble.

Between Houston and Livingston, most of US 59 is a limited-access freeway but the I-69 designation temporarily ends at the Montgomery-Liberty county line.

Ten miles (16 km) north of Lufkin, US 59 bypasses Nacogdoches and heads in an almost entirely east–west direction.

Drivers wishing to stay on US 59 must turn left in Tenaha, where the highway intersects US 96 and ends its overlap with US 84.

The entire I-69 project in Texas does not have a completion date but according to rules from American Association of State Highway and Transportation Officials (AASHTO), it should be within 25 years of initial signage for each Segment of Independent Utility.

US 59 has eleven designated business routes in Texas, between Carthage and its southern terminus in Laredo.

It was commissioned on May 25, 2023, from a former alignment of US 59, after that route was redesignated along a freeway bypass to the east of the cities.

[16] The loop was first designated on November 3, 1972, when US 59 was moved onto a bypass on the northwest side of town.

The loop was designated on October 29, 1998, after US 59 was re-routed on an expressway along the northwest side of town.

The loop was formed on April 23, 1997, after US 59 was rerouted on the southeast side of town on a new expressway.

The route was formed on January 26, 1995, along a former section of US 59 through Victoria after US 59 proper was rerouted onto the southeastern segment of Loop 463.

US 77-S continue concurrently past both the southern termini of FM 236 and FM 1685 respectively, crossing a divided four-lane bridge over the Guadalupe River, then enter Victoria through the southwest side of town.

The loop was originally formed when US 59 was rerouted south of downtown George West on March 28, 1989.

The loop continues six blocks east, crossing the railroad tracks, then curves southeast, ending at the US 59 expressway, outside of George West.