The crash occurred just before 4:00 a.m. Friday at Mile Marker 8, located between Lawrence and Reed Roads.
According to investigators, a gold Oldsmobile Royale was travelling the wrong way on the northbound Blue Route when it collided head-on with a Chevrolet Venture in the left lane.
The vehicles were then struck by two oncoming tractor-trailers.
Both drivers of the head-on crash were pronounced dead at the scene.
Police have not released the identities of the victims, but say the driver of the Oldsmobile was from Philadelphia and the driver of the Chevrolet was from Delaware City, Delaware.
Neither operator of the tractor-trailers involved was injured.
The crash had the northbound lanes of the highway closed for almost three hours while crews worked to clear the scene. Traffic finally reopened just before 7:00 a.m.
The crash remains under investigation.
