About 3:18 a.m., multiple callers reported a dark-colored Honda sedan traveling northbound on the southbound side of the interstate, just south of the 91 Freeway, according to the California Highway Patrol.
The violent collision occurred minutes later when the wayward car slammed into a Chevrolet Suburban, which then overturned and hit a K-rail near the center divider. The two mangled vehicles erupted into flames.
Anaheim Fire Department firefighters responded to the scene and extinguished the blaze.
Both drivers died at the crash site. They were identified only as a man in his 50s in the Chevrolet and a man in his mid-20s in the Honda.
All southbound lanes were initially closed after the incident. The CHP issued a SigAlert and later reopened the carpool lane.
All lanes were reopened shortly after 7:30 a.m., according to the highway patrol.