Interstate 5 and State Route 99 run the length of District 6, serving as the main north-south arteries for not just the Central Valley, but for the entire state as well. These two routes carry a significant amount of truck traffic that is vital to the agricultural base of the region.

State Route 41 connects Madera and Fresno counties with Kings and Kern counties, passing through the cities of Fresno, Kettleman City and Bakersfield. It also provides access to Yosemite National Park and the Central Coast.

State Route 43 runs parallel to SR 99 and I-5, connecting Shafter in Kern County with Selma in Fresno County. It passes through the towns of Wasco, Corcoran and Hanford along the way.

State Route 58 crosses District 6 from east to west, linking Bakersfield with Mojave in Kern County and Barstow in San Bernardino County. It also serves as a major commuter route for residents of Tehachapi and Boron.

State Route 198 connects Visalia in Tulare County with Coalinga in Fresno County, crossing the Diablo Range and the San Joaquin Valley. It also provides access to Sequoia National Park and Lemoore Naval Air Station.