California Highway Patrol Madera says there was an initial crash just before noon on Saturday that involved nine cars near Highway 99 and Ave 16.
Traffic was backed up southbound due to the accident.
Shortly after, around 1 pm, there was another accident involving three cars near Highway 99 and Ave. 20 1/2.
Authorities say the three cars rear-ended each other due to the halted traffic.
Four people in total were sent to Community Regional Medical Center. Two have minor injuries and the other two were life-flighted with major injuries.
Traffic is currently flowing slowly but drivers are expected to have delays southbound on Highway 99.