Interstate 35 northbound begins at an intersection (controlled by a stoplight) with Business Spur I-35 in Laredo, Texas, just north of the Rio Grande. Through Webb, La Salle, and Frio Counties, it has a mostly north-northeastern course, turning more northeast around Moore. It then cuts across the corners of Medina and Atascosa Counties before entering Bexar County and San Antonio.
Interstate 35 is named the Pan Am Expressway in San Antonio. There, it has brief concurrencies with both Interstate 10 and Interstate 410, and serves as the northern terminus of Interstate 37. I-35 heads northward out of the city towards the state capital, Austin.
In Austin, Interstate 35 is the Interregional Highway. Throughout Austin, elevated express lanes were constructed on either side of the original freeway. Prior to this expansion, this section included an at-grade railroad crossing, which is extremely unusual for a freeway. From Austin, I-35 goes through Round Rock, Temple, and Waco. In Waco, I-35 is the Jack Kultgen Freeway.
I-35 then heads to Hillsboro, where it splits up into I-35W and I-35E and runs through the Dallas/Fort Worth area. The official mile markers follow I-35E through Dallas¡ªI-35W, which is 85 miles in length, carries its own mileage from Hillsboro to Denton, as though it were an x35 loop. In Dallas, I-35 is the R.L. Thornton Freeway south of I-30, which picks up the name heading east. North of I-30, it is the Stemmons Freeway.
After passing through D/FW, I-35's two forks merge in Denton. The unified interstate then continues north to Gainesville before crossing the Red River into Oklahoma.
In Oklahoma, I-35 runs from the Red River at the Texas border to the Kansas line near Braman, passing through many of the state's major cities, including Ardmore and the cities of the Oklahoma City Metropolitan Area such as Norman, Guthrie, Edmond, and the state capital and largest city, Oklahoma City. In Downtown Oklahoma City, I-35 has a major junction with I-40 and spurs into I-235 through the north central inner city.
Between the Oklahoma state line and Emporia, I-35 is part of the Kansas Turnpike. This section of interstate serves Wichita and passes through the Flint Hills area. At Emporia, I-35 branches off on its own alignment. This free section of I-35 provides access to Ottawa before entering the Kansas City Metropolitan Area, where it serves Johnson County, and Kansas City, Kansas.
I-35 enters Missouri near downtown Kansas City and serves as the west and north legs of the Downtown freeway loop. Along the north edge of the loop, I-35 joins with I-70. Upon leaving the loop, Interstate 29 begins, concurrent with I-35. The two interstates cross the Missouri River together on the Paseo Bridge.
After crossing the river, I-29 and I-35 split. I-35 heads north to Cameron, Missouri, and then continues northward to the Iowa state line.
I-35 is part of the Avenue of the Saints between Clear Lake and St. Paul, Minnesota. A four-lane link has been completed between Clear Lake and Interstate 380 in Waterloo, Iowa.
In the southern sections of the state, I-35 is parallel to U.S. Route 69, for much of its course. The highway runs mostly on a north alignment.
In Des Moines, I-35 has a 12 mile overlap with I-80. The concurrency takes place northwest of the downtown district of the city. At exit 127 of I-80, the overlap turns east and terminates at exit 137 via an interchange with Interstate 235.
North of Des Moines, I-35 is mainly parallel with US 69, traversing a vast and rural area of Iowa.
The Minnesota section of Interstate 35 and Interstate 35W respectively are defined as legislative routes 390 and 394 in Minnesota Statutes ¡́ 161.12(2). The roads are not marked with those numbers. All of I-35 in the state of Minnesota from the Iowa state line to Duluth is named the Red Bull Highway, after the 34th Infantry (Red Bull) Division.
At Medford, Minnesota, the on/off ramps lead to roundabouts rather than standard cross intersections. This is the first site in the state linked to a major highway to use roundabouts.
I-35 splits again into I-35W and I-35E in the Minneapolis/Saint Paul, Minnesota area. The mile- and exit-numbering sequence continues along I-35E. At one sharp turn in I-35W near the junction with I-94, it is advised to slow to 35 mph (55 km/h) (although many drivers are able to maintain the speed limit of 55 mph (90 km/h)). Additionally, it is not possible to go from westbound I-94 to northbound I-35W, from southbound I-35W to eastbound I-94, from eastbound I-94 to southbound I-35E, and from northbound I-35E to westbound I-94 without resorting to surface streets.
On I-35E in Minnesota between Minnesota State Highway 5 and Interstate 94, in both directions, trucks weighing more than 9,000 lbs (4,082 kg) are banned from the freeway, and the speed limit drops to 45 mph (70 km/h) but it is rarely obeyed. This section was not completed until the late 1980s (although the route was cleared and graded earlier) due to opposition from the historic Crocus Hill neighborhood which sits only a few hundred feet from the alignment. The four-lane alignment, "parkway" design was a compromise. The truck bypass for this section is signed on I-494 and I-694 to the east of Saint Paul.
The I-35 / I-535 / U.S. 53 interchange in Duluth, Minnesota is known locally as the "Can of Worms" and features a pair of left exits from I-35, a stoplight, and lane drops over the I-35 bridge.