Officers were sent to Devonshire Street and Etiwanda Avenue about 9:50 p.m. Thursday, according to the Los Angeles Police Department.
"A motorcyclist was traveling at a high rate of speed eastbound Devonshire Street from Etiwanda Avenue," police said in a statement. "As the motorcyclist approached Louise Avenue, he failed to stop for a red tri-light and collided with a vehicle traveling northbound Louise Avenue."
Police said the motorcyclist was ejected onto westbound lanes of traffic on Devonshire and was hit by a pair of westbound vehicles.
The first vehicle was described as a white SUV, and the second as a white sedan.
"Both (drivers) failed to stop, identify themselves or render aid, as required by law," police said.
The injured man, in his early 20s, died at the scene. His name was withheld, pending notification of his relatives.
A standing reward of up to $50,000 has been offered by the city of Los Angeles for information that helps solve a fatal hit and run.
Anyone with information on the case was urged to call Valley Traffic Division Investigators Takishita or Ramirez at 818-644-8116, or 877-LAPD-247. Tipsters may also call Crime Stoppers at 800-222-TIPS, or use the website www.lacrimestoppers.org.