The Union Pacific freight train's engine was also turned onto its side, with the rest of the train splayed out like an accordion behind it.
Mayor Antonio Villaraigosa said at the scene there were between 10 and 15 fatalities, and 50 to 60 people injured.
"This is the worst accident I've ever seen," Villaraigosa said. "Clearly the injuries are going to mount and so are the fatalities."
Police Lt. John Romero said the death toll was 10 to 20.
The crash "made a terrible sound, like a bomb, a huge noise," said Julio Pedraza, 35, who lives and works at a nearby horse boarding facility. He said he saw passengers emerging from the wreckage, and he and others helped the injured, one with skin peeling off of his forehead.
"They were yelling for help and crying," Pedraza said in Spanish.
Firefighters treated the injured at three triage areas near the wreck, and helicopters flew in and out of a nearby landing area on medical evacuation flights.
Rescuers worked atop the wreckage and through breaches in the passenger car to reach victims. Dazed and injured passengers sat on the ground and milled about on both sides of the tracks.
Surgeons were sent to the scene.
Dr. Stephanie Hall, chief medical officer at Los Angeles County-USC Medical Center, said three people in critical condition - two females and a male - were being treated at the hospital.
"They are massive injuries," she said.
One of the largest medical facilities in the area, Northridge Hospital Medical Center, was told to prepare for the arrival of injured passengers, said hospital spokeswoman Christina Zicklin.
"We are expecting some people. I don't know the number yet," she said.
A male passenger told KNBC-TV he boarded the Metrolink train in suburban Burbank and was talking with a fellow passenger when the crash occurred.
"Within an instant I was in my friend's lap. It was so quick. It was devastating," he said. The man was visibly injured, but able to walk with the aid of firefighters. The man said he was involved in a devastating 2005 Metrolink crash in Glendale and was talking about it with the other passenger when Friday's crash occurred.
The trains collided in the Chatsworth area of the San Fernando Valley.
Metrolink spokeswoman Denise Tyrrell said the train left Union Station in downtown Los Angeles and was headed northwest to Moorpark in Ventura County. She couldn't confirm how many people were on the train, but said that in rush hours there would usually be about 350 people on board.
"We don't know if we hit another train or another train hit us," Tyrrell said.
She said the Metrolink train was being pulled by its locomotive rather than being pushed. The push mode is controversial due to claims that it makes trains more vulnerable in accidents.
The condition of the freight crew was not immediately known.
Union Pacific spokeswoman Zoe Richmond said a freight train usually has a two-person crew.
She also said it is common in California for freight and commuter trains to share the same track.
"You see it a lot in California where commuter trains share tracks with freight trains," Richmond said, adding she couldn't speculate about the cause of the crash.
The federal investigation into the crash will be headed by the National Transportation Safety Board, said Steven Kulm, a spokesman for the Federal Railroad Administration. The FRA will conduct a review of whether any federal rail safety regulations were violated, he said.
Asked about how the two trains ended up on the same track, Kulm said, "We are nowhere near having any information on that."
The crash happened in an area where the tracks form a "U" shape, about 2,500 feet wide. At the top of the bend is a 500-foot long tunnel that runs beneath Stoney Point Park, popular with climbers for its large boulders.
The toppled passenger car was part of a Bombardier BiLevel coach, commonly used for regional railways from Seattle's commuter rail Sounder to New Jersey Transit. Each double-decker car is about 16 feet high and 10 feet wide and can seat up to 160 passengers, depending on its configuration.
The worst disaster in Metrolink's history occurred on Jan. 26, 2005, in suburban Glendale, when a man parked a gasoline-soaked SUV on railroad tracks. A Metrolink train struck the SUV and derailed, striking another Metrolink train traveling the other way, killing 11 people and injuring about 180 others. Juan Alvarez was convicted this year of murder for causing the crash.
Associated Press writers Raquel Maria Dillon, Greg Risling, Denise Petski, Josh Dickey, James Beltran and John Rogers contributed to this report.