The accident happened just before Route 24, near where the express and local lanes split, at about 3:30 p.m., according to police.
One vehicle was apparently traveling westbound on I-78 when it left the highway and crossed through the center median into the other direction of travel. It crashed through the guardrail and struck head-on a vehicle going eastbound, pushing it all the way over to the right shoulder.
One woman was sent to the hospital in an ambulance, and a man was airlifted to the hospital with serious injuries.
The highway was closed so the helicopter could land. Lanes are expected to stay closed for another hour. Westbound lanes are getting by without a problem.