Immediately after splitting from US 101, SR 46 crosses the Salinas River, passing near the Paso Robles Municipal Airport, and then heads east through a hilly area with several wineries and the community of Whitley Gardens.

After crossing into Kern County, the highway continues to rise as it heads east up the Antelope Grade to a summit near Bluestone Ridge before descending through Polonio Pass into the San Joaquin Valley.

[13] An extension west to Route 56 (now SR 1) near Cambria was added in 1933;[14][15] however, it ran along Santa Rosa Creek Road, north of today's alignment.

[16] The two-lane stretch from Paso Robles to Cholame was known as "Blood Alley" for the large number of vehicle incidents, mainly head-on collisions, among the high volume of commuters, truck drivers and tourists.

[26] The California State Legislature dedicated that intersection as the James Dean Memorial Junction on September 30, 2005, for the 50th anniversary of the actor's death in a car crash near that site.

[28][29] The California Department of Transportation (Caltrans) carried out an interim safety project west of Cholame in December 1995, mandating daytime headlights and installing thermoplastic striping, a concrete barrier and rumble strips.

On April 25, 2023, workers broke ground on constructing a new grade-separated interchange at the James Dean Memorial Junction, which is scheduled to be completed in 2026.

The 3.6 mi (5.8 km) portion of SR 46 leading to Kern County, known as the Antelope Grade Section, is scheduled to begin construction in 2026.

[33][34][35] 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.