The highway passes through the cities of Cotulla, Dilley, Pearsall, Devine, and Lytle before reaching San Antonio.

It rejoins the lanes as it goes through an intersection at the northeast corner of Downtown, where I-37's northern terminus is located, while US 281 will continue on the north–south freeway.

It merges with I-410 on its eastern north–south leg from its northbound direction in a triangular interchange and continues north concurrently from there.

A few miles later, I-410 will split off onto its northern west–east leg, while I-35 resumes its north-northeast course past the northeast corner of the city.

It forms the eastern boundary of Downtown Austin and also passes through the eastside of the University of Texas campus.

The I-35 corridor between San Antonio and Austin is considered one of the most congested stretches of highway in the Interstate System.

Efforts to alleviate the congestion include State Highway 130 (SH 130), which forms an I-35 bypass loop to the east of Austin.

Many local and regional governance organizations have ongoing studies on other methods to improve mobility on I-35, which include such features as commuter rail lines and additional managed lanes.

[9] In 1975, a two-mile (3.2 km) set of elevated express lanes were added to I-35 between 15th Street and Airport Boulevard.

[10] The reason double-decking was used is because the highway is bounded in the area by the University of Texas campus on the west and by the Mount Calvary Cemetery on the east, restricting the available right-of-way.

The lower deck kept its original configuration, which featured short on- and offramps with limited visibility.

In 2000, some offramps on the lower deck were removed in response to the already dangerous conditions becoming more so as traffic levels on the road increased.

[12][13] I-35, at one time, had one of the few at-grade railroad crossings in the Interstate Highway System, near Airport Boulevard in Austin.

[14][15] The northern interchange at SH 45 was partially affected by a tornado on March 21, 2022, when a large light pole was ripped off its foundation, the debris resting on the side of a flyover, as seen from photos captured by KXAN-TV.

[16] Construction on I-35 in the Dallas–Fort Worth region began around 1960 with the upgrading of US 77 to Interstate standards between Dallas and Denton.

[17] It also calls for complete replacement of the mainlane bridges over the Brazos River and extensive renovations to frontage roads and interchanges throughout the corridor.

Construction largely wrapped up in the middle of 2019 with the completion of the Temple segment except for the portion of freeway running through the Downtown Waco area.

[20] The $500 million Capital Express North project is set to begin construction in late 2022 and runs from SH 45 north to US 290 east, adding one high-occupancy vehicle lane (HOV lane) in each direction, reconstruction of six bridges, and a new diverging diamond interchange at Wells Branch Parkway.

[24] Critics of the expansion are requesting TxDOT study alternate proposals, including re-routing I-35 traffic along SH 130, or removing the highway and replacing it with an at-grade boulevard through central Austin.