It happened near Exit 136 on the Garden State Parkway in Clark Township.
Police said a car overturned, then ended up in the Rahway River.
Rescuers pulled the victims from the vehicle, but authorities say it was too late. The identities of the victims are not being released at this time.
The crash is causing serious traffic delays in the area, and lane closures are expected to remain in place for an extended period of time.