The incident happened around 12:30 a.m. on Bethlehem Pike (Route 309).
It was a box truck carrying a drum of Ammonia Hydroxide fluid that was stopped after the leak was discovered, police say.
Ammonia Hydroxide is an irritant to eyes and skin.
HAZMAT crews on the scene say, this will be an extended operation because the chemical is difficult to clean up quickly.
PennDOT crews were also called to the scene.
The road is closed in both directions of Route 309 between Broad Street and Richardson Road.
Commuters should expect delays and make alternate travel plans.