It happened before 1:30 am near Atwater Boulevard.
California Highway Patrol officers said the truck was southbound on the highway in a road construction area. Investigators believe the truck driver's speed led to the deadly crash.
"The big rig swerved at the last minute to go into the number two tunnel. It struck the sand barrels that were in front of the temporary K-rails at the point of the offramp, which caused the big rig to overturn on its side and come to rest behind us," said CHP Sgt. Shane McConnell.
Officers say the driver was not wearing a seat belt and was thrown from the vehicle. He ended up pinned underneath the truck's cab as it flipped onto its ride side.
He was pronounced dead at the scene.
The big rig usually hauled wine, but the tanker was empty.
One lane of Highway 99 is currently open as crews continue to clear the sand from the roadway.
Click here for map of the latest traffic conditions on Highway 99.