The driver of the semitruck was hospitalized following the crash, which happened about 3:50 p.m. on Highway 24 near state Highway 13, according to the California Highway Patrol.
The collision was triggered when a Subaru made an unsafe lane change into the path of a Nissan, the CHP said.
The Subaru slowed to a stop due to traffic and was rear-ended by the Nissan, which was then struck by a Peterbilt big-rig towing a 53-foot trailer filled with cardboard, according to the CHP.
The big-rig overturned and then a Ford pickup truck was hit by cardboard from the overturned semi. The big-rig came to rest blocking all lanes on Highway 24.
Traffic was diverted to northbound Highway 13 until the westbound lanes on Highway 24 reopened about 6:15 p.m.
The driver of the big-rig had a complaint of pain in a right leg and a left arm, and was transported to Highland Hospital.
No other injuries were reported, the CHP said.