All lanes of U.S. Highway 101 near the Redwood Sanitary Landfill have been reopened.
The crash was initially reported to be in the northbound lanes, but it occurred in the southbound lanes.
Emergency responders found three vehicles were involved in the crash.
Officers said the preliminary investigation into the crash revealed a man in a 1995 Toyota Camry wagon was traveling the wrong way on the highway and was approaching the Redwood Sanitary Landfill over crossing when he crashed head-on into a 2013 Nissan Sentra with a male driver and female passenger.
Investigators said both vehicles were traveling at freeway speeds.
After the collision, the Toyota came to rest in the center divide, and the Nissan overturned, was hit by a 2006 Dodge Ram pickup truck heading south and ended up on its roof in a ditch.
The drivers of the Toyota and Nissan were both pronounced deceased at the scene.
The woman passenger of the Nissan was transported to the hospital with moderate to major injuries.
The driver of the truck was not injured. The highway was shut down for several hours as crews worked the scene.
Officers said investigators believe alcohol was a factor in the crash.
The identities of the deceased people have not been released.