Authorities say the SUV blew a tire, ran off the highway between Four Oaks and Benson, and hit a tree before overturning in the woods.
Rescue workers had to use the Jaws of Life, and other heavy equipment to reach the victims, who were from New Jersey.
There were seven people in the SUV heading to a funeral in South Carolina. Three were taken by ambulance to the hospital.
The Highway Patrol shut down the interstate so a fourth person could be air lifted to a trauma center.
I-95 was closed for about 30 minutes.