Two others were injured.
The southbound driver of a tan Honda Civic apparently ran a red light at the intersection of Valley Parkway and Broadway around 11:15 a.m., and collided with a westbound white Toyota Corolla, according to Escondido police.
Both vehicles came to a rest on the southwest sidewalk.
Arriving officers found the Honda's driver without a detectable pulse and not breathing, Escondido police Lt. Justin Murphy said.
Officers tried to remove the seatbelted driver from the wreckage, but were unable to because the car was so badly damaged.
One of the officers, a former Emergency Medical Technician, attempted to resuscitate the driver in the seat until medics arrived, Murphy said.
However, that driver later died at Palomar Hospital.
No name or gender were immediately released.
The Toyota's driver and a passenger were also hospitalized following the crash.
Murphy said both were treated for minor injuries.
Alcohol was not a suspected factor in the crash, according to the lieutenant.