The California Highway Patrol (CHP) says the crash happened just after 6 pm on Saturday on the I-5 near Nees Avenue west of Firebaugh.
Authorities say the man was heading north on the highway when he lost control of the truck and went off the left side of the Nees off-ramp.
Despite wearing his seatbelt, the man suffered severe injuries and was pronounced dead at the scene.
The CHP says it is unclear what caused the driver to lose control, but speed, alcohol, or drugs are not believed to have been factors.
The man is from Oregon, the CHP says.