The single-vehicle crash occurred around 2:30 a.m. Tuesday. Sheriff's officials say the deputy, 31-year-old Jeremy Meyst, was ejected from a van after apparently hitting a cement guardrail on the road.
The California Highway Patrol is investigating what led to the crash. The two inmates suffered minor injuries.
Meyst, a correctional deputy, was transporting the inmates to the main jail from the department's Porterville substation. Sheriff's officials say there is no indication the inmates had any role in the crash.
In a statement, Sheriff Mike Boudreaux said Meyst's death left him heartbroken. Meyst is survived by his wife and two young children.