The collision was reported shortly before 2 a.m. near Newcomb's Ranch and the Devil's Canyon trailhead, according to the California Highway Patrol.
The crash was reported from a call box about 10 miles away from the crash site, where there was no cellphone service, the CHP said.
Los Angeles County Fire Department firefighter-paramedics responded to the scene and pronounced two individuals dead. The deceased were not immediately identified.
A third person was transported to a hospital in unknown condition, the Highway Patrol said.
Video: Fight breaks out on 60 Freeway in Ontario after crash, officer tackles men to ground
Video: Fight breaks out on 60 Freeway in Ontario after crash, officer tackles men to ground
Video from AIR7 HD showed CHP officers examining the wreckage of a silver sedan. Both sides of the vehicle were mangled and the windshield was shattered, but the front end of car remained intact.
The cause of the incident is under investigation.