Officials attended the scene after 2:30 a.m. at the eastbound interchange between I-565 and U.S. 72.
A vehicle traveling westbound in the eastbound lanes on I-565 may have caused the crash.
The wrong-way driver first hit a vehicle, killing a passenger in the vehicle it struck. After striking the first vehicle, the driver then hit a second vehicle, resulting in the death of the person in second vehicle.
The identities of the victims were not released as of yet.
Huntsville Police Department is investigating the crash.