Officials said the crash happened around 3:30 a.m. and for some time all lanes of the highway were blocked in the area.
The eastbound lanes of the expressway were closed for several hours after as officials continued to investigate.
Traffic was backed up for miles from Route 202 to the approach to the Blue Route as drivers sat in wait on the expressway near Gulph Mills.
Crash shuts down portion of Schuylkill Expressway
At 5:30 a.m., police said they expected some of the lanes to reopen shortly, but the roadway did not officially reopen until almost two hours later.
Officials report at least two people were injured in the crash, one of whom was taken to the hospital.
A van from the coroner's office was called to the scene during the investigation.
There is no word yet on the conditions or the number of occupants to vehicles involved in the wreck.