Also see Interstate 69 in Texas

In the U.S. state of Texas, U.S. 59 is named the Lloyd Bentsen Highway, after Lloyd Bentsen, former U.S. Senator from Texas. In northern Houston, US 59 (co-signed with Interstate 69 in Texas) is the Eastex Freeway (from Downtown to Humble). To the south, it is the Southwest Freeway (from Rosenberg to Downtown Houston), which is one of the busiest sections of freeway in the United States with a vehicle count, as of 2006, over 330,000 vehicles per day just outside the Loop. To make things more confusing, 70 miles to the east, in Beaumont, Texas, U.S. 69, heading north of IH 10, is also officially known as Eastex Freeway, and is an evacuation route, as well.

US 59 (overlapped by US 71) actually straddles the border between Texas and Arkansas north of Interstate 30 near Texarkana, with the east side of the highway in Arkansas and the west side of the highway on the Texas side. In the past, both highways remained on the border past I-30 as State Line Avenue to downtown Texarkana; today, only US 71 does so. Nearly 90% of this route is designated to become part of Interstate 69 in the future. Currently 75 mph is allowed on US 59 in Duval County only.

The total length of the southernmost segment of U.S. Route 59 that passes through Texas and terminates near the Mexican border is some 615 miles.

The US 96 designation was originally applied in 1926 from Rosenberg, Texas, near Houston to Pharr in the Rio Grande valley. This diagonal route, south of U.S. 90, did not violate the convention of even numbers for east–west routes. The highway's east–west nature was boosted in 1934 when US 96 was rerouted from Alice to Laredo.

US 59 begins in Laredo at an intersection with I-35 about 2 miles north of the Mexican border. Traveling in a mostly northeast direction, US 59 intersects Loop 20 just north of Laredo International Airport heads towards Freer. In Duval County, the speed limit on US 59 is 75 miles per hour, the highest speed limit on the highway. US 59 shares a short congruency with SH 44 in and around Freer. From Freer, US 59 passes through the southeastern part of McMullen County, but does not intersect any highways. The highway continues northeast, intersecting US 281 in George West, before intersecting I-37 about 55 miles north of Corpus Christi. Between Laredo and Interstate 37, US 59 passes through many rural areas and ranching sites.

From I-37, US 59 heads northeast passing through Beeville. US 59 bypasses Victoria to the south, and becomes a divided highway, and has a series of interchanges, until it becomes a freeway south of Houston in Rosenberg. Between Houston and Victoria, US 59 passes through Edna, 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).

Future I-69 overlaps US 59 north of Houston and through Montgomery County; the portion from Rosenberg through Houston has been submitted for designation and is awaiting approval.

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. US 59 passes through or bypasses the towns of Cleveland and Livingston. 46 miles north of Livingston, US 59 bypasses Lufkin, where it overlaps US 69. 10 miles 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. US 59 passes through Carthage before intersecting I-20 south of Marshall.

US 59 intersects US 80 in Marshall, where US 59 is known as East End Boulevard (due to the fact the highway runs on the east side of town, near the city limits). US 59 passes through Jefferson, 15 miles east of Caddo Lake. US 59 passes through the towns of Linden and Atlanta before arriving in Bowie County. US 59 intersects SH 93 south of Texarkana, the old highway through the city. Shortly after, US 59 intersects Spur 151, where US 59 becomes a freeway on the westside of the city. US 59 intersects I-30, and overlaps I-30 until exit 223B, at the state line. After leaving I-30, US 59 joins US 71, where both highways run on the state line between Texas and Arkansas, where both highways continue north towards DeQueen, Arkansas.