The multi-vehicle collision was reported around 11 p.m. Wednesday on the westbound 10 Freeway near Wildwood Canyon Road, according to Caltrans. Several people were hospitalized in unknown conditions.
Officials said the crash was caused by winter conditions, including icy slush that was seen on the road.
Snow is rare in the area, and more expected over the next 48 hours.
"We are anticipating getting a lot of snow, the mountains are going to have hazardous winter weather conditions with chain-control," said Cal Fire Battalion Chief Grant Malinowski. "Down here in the city, where we don't necessarily have chain-control, folks just need to be very cognizant to drive slow, drive careful... Stay at home if you can."
The pile-up shut down all lanes of the freeway, but they have since reopened.
SoCal mountains get hit with heavy snow, causing pile-up crash on Highway 189
Another pile-up on Highway 189 just outside of Crestline stranded drivers Wednesday night. More than a dozen vehicles were involved in that chain reaction crash on the snow-covered road.
The road was blocked for more than four hours.
This comes as the region braces for even more severe weather conditions in mountain communities and other areas.
A blizzard warning is set to go into effect at 4 a.m. Friday, the first issued for Los Angeles County mountains since 1989.