The crash was reported at about 7:20 a.m. on Highway 1 at the Market Street overpass, according to the Santa Cruz Fire Department.
Arriving firefighters found a minivan engulfed in flames and another vehicle overturned on its roof, the fire department said.
One person was flown to a trauma center by air ambulance, and a second victim was taken to a hospital via ground transportation, the fire department said.
The fire was extinguished and prevented from spreading to nearby vegetation.
Southbound Highway 1 was shut down for about 30 minutes while the roadway was cleared.
The cause of the crash remains under investigation by the California Highway Patrol.