It happened around 4:30 a.m. in the northbound lanes near Route 841.
Police said one of the drivers was trapped and had to be extricated while the other was ejected from the vehicle.
Both drivers were transported to area hospitals in serious condition.
Pennsylvania State Police are redirected traffic in the area as the northbound lanes of the bypass were closed for several hours following the incident.
The cause of the crash is still under investigation.