The tanker truck was used to carry aviation fuel but was empty at the time of the incident.
The truck was traveling southbound on the busy highway before it crashed onto the street below at around 7:30 am.
The driver of the tanker was injured and taken to a hospital, but the extent of his injuries are not yet known.
At this time it is not known what caused the big rig to careen off the highway, but the California Highway Patrol is looking into three other vehicles that may have been involved.
"What we do know is at one point, when (the truck) leaves the roadway, a good portion of the component from the vehicle gets launched back out onto the freeway and hits another big rig," said Sgt. Leonard Sherman of the California Highway Patrol. "There's also a collision between two cars, two passenger vehicles, but we are not sure what happened first."
Both directions of Highway 41 were briefly closed after the accident, but have since reopened. Van Ness is expected to be closed for a few hours as crews work to remove the wrecked truck.
This story will be updated.