Seven rear cars, two of them passenger cars, apparently jumped the track about 5:30 a.m. just east of Palm Springs and some 110 miles east of Los Angeles.
There were at least two injuries, which Amtrak spokesman Cliff Black described as minor bumps.
None of the cars on the westbound Sunset Limited from Orlando, Fla., to Los Angeles tipped over, Black said. The train's speed wasn't immediately known and the cause was not clear, he added.
"We have ordered buses to take passengers to their destination," Black said.
The train consisted of three engines and 16 cars, which included five "express cars" at the rear carrying mail and packages. Two rear passenger cars and five express cars slipped off the track.
On Saturday, another Amtrak train derailed some 125 miles northeast of Los Angeles after the region was shaken by a magnitude-7.1 earthquake. Four of the 155 passengers on the Chicago-to-Los Angeles train suffered minor injuries.
Friday's derailment had nothing to do with Saturday's quake, Black said. The two sites are about 50 miles apart.