The Ventura Freeway begins at the Santa Barbara/Ventura county line, west of La Conchita, as US 101.

Continuing eastward through the northern Santa Monica Mountains, it crosses the Ventura/Los Angeles county line before entering the San Fernando Valley.

The westernmost portion of the freeway also forms part of the unsigned SR 1 concurrency that stretches from Las Cruces in the west to Oxnard in the east, with SR 1 spitting off for about 6 miles (9.7 km) to serve Sea Cliff, Faria, Solimar Beach, and Emma Wood State Beach.

[6] A pre-freeway alignment of State Route 134 originated at U.S. Route 101 (Ventura Boulevard) and Fulton Avenue in Los Angeles, then along Fulton, Moorpark Street, Riverside Drive and Alameda Avenue before meeting up with U.S. 6/99 (San Fernando Road) in Burbank.

Old SR 134 continued onto the ramp and then onto what is presently the Ventura Freeway to Orange Grove Boulevard in Pasadena.

At the freeway's eastern terminus with Interstate 210 in Pasadena, highway signs indicate "Ventura" as the destination direction for Route 134.

Assembly Concurrent Resolution 54, Chapter 85 in 2003 also designated Route 101 in Ventura County as the "Screaming Eagles Highway".

[8] The California Legislature passed a resolution in 2017 to designate the easternmost segment of the SR 134 freeway between SR 2 and its terminus at I-210 as the "President Barack H. Obama Highway", in honor of the 44th U.S. President Barack Obama, who had attended Occidental College in Eagle Rock from 1979 to 1981.

[11][12] Ventura Freeway currently carries the Los Angeles Metro express bus route 501 between Pasadena and North Hollywood.

Except where prefixed with a letter, postmiles were measured on the road as it was in 1964, based on the alignment that existed at the time, and do not necessarily reflect current mileage.