The crash, which involved a motorcycle, was reported near the Skirball Center Drive off-ramp at 8:53 p.m. Tuesday.
A 45-year-old man was pronounced dead. Two victims were transported to local hospitals in fair condition.
The freeway was shut down in both directions between Sunset and Valley Vista boulevards, but all lanes reopened just before 2 a.m. Wednesday, according to the California Highway Patrol.
The CHP is handling the investigation.