Authorities responded to the scene near 37th Street and Santa Fe Avenue at about 3:10 a.m., according to Vernon police.
Investigators said the driver of the 18-wheeler ran a red light before he or she collided with a pickup truck that was found lodged underneath the trailer of the big rig.
According to authorities, the suspect apparently detached the cab from the trailer and fled.
Two men were found trapped inside the pickup truck. The driver was removed from underneath the trailer and transported to USC Medical Center in critical condition, police said. The passenger of the truck was pronounced dead at the scene.
Police said the driver had been involved in a minor crash near Soto and 37th streets shortly before the deadly incident.
No further information was available as the investigation was ongoing.