The crash happened in the northbound lanes of the highway at mile marker 51.8 just before 9 a.m.
According to New Jersey State Police, a Jeep Compass being driven by 62-year-old Stanley Kahana of Philadelphia was traveling southbound when, at an unknown location, his vehicle crossed into the northbound lanes.
His Jeep traveled the wrong way on Route 55 North until it collided with a Toyota Rav 4 being driven by 53-year-old Jennifer Hufnell of Deptford, N.J.
Both vehicles overturned and the Toyota caught fire, police say.
Kahana and Hufnell were killed in the crash.
Video taken by a driver in the southbound lanes shows the Jeep traveling the wrong way before it collides with the Toyota head-on.
Video from Chopper 6 showed the Jeep its roof in the median.
The Toyota landed on its side along the shoulder. Debris and pieces of the cars were scattered all over the road.
Drivers were re-routed to avoid the closure.
"We were sitting in traffic for quite a while. A lot of police cars went by, fire trucks went by, and then they re-routed us off and sent us the other way," said Steve Anderson of Vineland.
An investigation into the circumstances of this crash continues.