After merging with westbound traffic from the San Bernardino Freeway (I-10), US 101 then proceeds northwest via the Downtown Slot under the northern edge of Los Angeles' Civic Center to State Route 110 (SR 110) at the Four Level Interchange.

From the Hollywood Split, US 101 is an east–west highway (until it reaches Gaviota State Park in Santa Barbara County where it shifts back to a north–south alignment).

North of Santa Barbara, US 101 switches intermittently between freeway and expressway status (i.e. there is occasional cross-traffic), but there are no traffic signals until San Francisco.

A few miles north of the Gaviota Tunnel, SR 1 splits from US 101 and heads northwest, running along the Pacific coastline parallel and to the west of US 101.

Then US 101 takes an inland route through the Salinas Valley, while Highway 1 heads northwest, running along the Pacific coastline in California, parallel and to the west of US 101.

North of King City, US 101 once again switches intermittently between freeway and expressway status, passing through Greenfield, Soledad, Gonzales, and Chualar before reaching Salinas.

Upon exiting the tunnel, it passes above the hillside town of Sausalito and descends to Richardson Bay, where SR 1 splits from the freeway and heads to the coast.

US 101 crosses into Mendocino County as a freeway for one mile (1.6 km), but then narrows to an expressway through the Russian River canyon and eventually a two-lane road south of Hopland, the first time since leaving San Francisco.

The freeway portion ends as the combined US 101 and SR 20 ascend the 1,956-foot (596 m) Ridgewood Summit, the highest elevation along the route's 808-mile-long (1,300 km) trek through California.

This project, funded by an emergency act from the State Legislature, moved the highway across the Eel River away from the troubled spots to prevent disruption in commerce and travel from infrequent, but costly, winter closures on the main transportation route to the far North Coast.

Because of the narrow lanes and the redwood trees that tower over this segment of the highway, standard-sized trucks in compliance with the Surface Transportation Assistance Act (STAA) are prohibited through the park.

As the route traverses Eureka, the southern portion is known as "Broadway" and then as it bears east along Humboldt Bay, the Highway is aligned on a one-way couplet (4th and 5th streets).

The expressway style section between Eureka and Arcata, which is also a safety corridor, is named the "Michael J. Burns Freeway," in honor of the State Senator who was a proponent of California's Highways.

Proceeding north it passes the junction for SR 299 (also the western terminus for that route), in the Valley West (northernmost) part of the college town.

As the highway reaches Clam Beach (a county park), motorists get their first magnificent full view of the Pacific Ocean north of the Golden Gate.

The original highway segment through Prairie Creek Redwoods State Park is now a scenic alternate similar to Avenue of the Giants, named Newton B. Drury Scenic Parkway in honor of the fourth director of the National Park Service and executive director of the Save-the-Redwoods League North of the town of Klamath just inside Del Norte County, the highway closely follows the Pacific coast again.

As it leaves Crescent City, US 101 becomes a divided freeway for the last time in California (built slightly to the west of the original two-lane alignment, now called Parkway Drive).

US 101 (no longer called the "Redwood Highway" at this point) is reduced to two lanes and continues north along the California coast until it reaches the Oregon border.

High-occupancy toll (HOT) lanes along US 101 between SR 237 in Mountain View and Whipple Avenue in Redwood City opened on February 11, 2022.

Much of the route in northern San Diego County is County Route S21; this includes Coast Highway in Oceanside, Carlsbad Boulevard in Carlsbad, Coast Highway 101 in Encinitas, Camino del Mar in Del Mar, and Torrey Pines Road in Torrey Pines.

This freeway construction by the California Department of Public Works put US 101 on an all new highway route alignment to relieve Oceanside and Carlsbad of their very heavy bumper-to-bumper burdensome traffic problem.

Significant portions of US 101 from its southern terminus to the San Francisco Bay Area is designated as the Royal Road or El Camino Real.

The portion of US 101 starting from Los Angeles ends at "the approach to the Golden Gate Bridge" and then resumes at "a point in Marin County opposite San Francisco" to the Oregon state line.

[32] The primary control city that is listed on freeway signs along northbound US 101 through the Central Coast region remains San Francisco.

After the 1989 Loma Prieta earthquake damaged the structure, the segment of the Central Freeway north of Market Street was replaced with the surface-level Octavia Boulevard; traffic on US 101 was then eventually re-routed to exit south of that at Mission Street/South Van Ness Avenue.

In the wake of the dot-com bubble expansion, the segment of US 101 between Morgan Hill and San Jose, also known as the Sig Sanchez Freeway, expanded to eight lanes between Cochrane Road and SR 85 exits between 2001 and 2003 and a new interchange at Bailey Avenue, which had been planned since the 1970s, opened in 2004.

The following day, San Jose City Councilman Joe Colla was photographed standing next to the car, a photo which was circulated across many newspapers.

Construction was halted by US Army Corps of Engineers in June 2014 and work restarted the following month after Caltrans committed to extensive mitigation of the project.

A portion of the route between Cochrane Road in Morgan Hill and SR 85 in San Jose is named the Sig Sanchez Freeway.

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.