The solo vehicle crash occurred near the Colorado Street off ramp, according to California Highway Patrol officer Monica Posada.
The cause of the accident is unclear, but one man, identified as a 25-year-old Hispanic male, was ejected from the vehicle.
The driver and two passengers were rushed to the USC Medical Center with major injuries.
According to Posada, CHP officers are investigating the possibility that alcohol or drugs played a role in the fatal crash.
The Colorado Street off ramp was closed for the ongoing investigation.