The famed roadway was packed with beach traffic on Saturday when two vehicles collided just after 3 p.m.; then, eight more became entangled in the wreckage, Newport Beach police Lt. Bill Hartford said.
Three adults from two vehicles were declared dead at the scene; three others were taken to hospitals with injuries, one of them critical.
Two cars were overturned, some people were trapped inside their vehicles, and it took hours before some of the dead could be removed from the wreckage.
"Officers responding found glass strewn on both sides of the roadway, up onto the sidewalk, indicating a very violent traffic collision," Hartford said.
The names and ages of the dead and extent of the non-critical injuries were not immedicately available.
Officials told CBS Station KCBS correspondent Melissa Maynarich that the investigation into the cause of the crash will continue late into the evening, and that it will be "at least" until morning before traffic is allowed to go through the area again.
Newport Beach Police Lieutenant Bill Hartford on-scene told Maynarich, "This is very much a tragedy."
Sam Schudi was driving one of the cars involved, with his wife Kelli in the passenger seat. They say an oncoming car hit a car two vehicles in front of them and became airborne.
"I heard the screech and the sound, and all the sudden I saw this car come flying in the air," Kelli Schudi told KCAL. The couple was not among the injured.
The highway runs along the ocean through many of California's most scenic stretches and most expensive neighborhoods.