The food distribution truck crashed on the westbound side of the freeway near Monte Vista Avenue just after 11 p.m. Tuesday. At least two other vehicles - a Nissan and a Mercedes - were involved.
Authorities said it appears that the driver of the Mercedes possibly lost control and struck the big rig. The big rig then swerved to the left, hitting the Nissan.
The big rig burst into flames after hitting the center divider and spilling diesel fuel onto the eastbound lanes.
The big rig driver was pulled out of his vehicle by a passerby. The truck driver and the driver of one of the other cars were airlifted to the hospital with non-life threatening injuries, officials said.
At one point, all lanes were closed in both directions between Monte Vista Avenue and Indian Hill Boulevard. The eastbound side reopened just before 6 a.m. and westbound lanes reopened about half an hour later.
The cause of the crash remains under investigation.