It happened around 11:15 p.m. Monday on eastbound I-76 near the Girard Avenue exit.
Police said at least four vehicles were involved in the collision.
Responding crews rescued two people from the wreckage. They were taken to an area hospital with multiple injuries.
There is no word on the severity of those injuries.
The crashed closed the eastbound lanes of the Schuylkill Expressway as the investigation and cleanup took place. The roadway reopened by early Tuesday morning.