Footage on the East Coast city's NBC affiliate station showed plumes of smoke towering from the Philadelphia Energy Solutions (PES) refining complex.
The blaze in south Philadelphia broke out around 4:00 am (0800 GMT) when a series of explosions occurred, according to NBC10. The fire could be seen for miles.
Refinery authorities say they are still working to account for all plant staff, the network reported.
Philadelphia's Office of Emergency Management asked residents and workers at businesses east of the scene to remain indoors until further notice.
A major highway was briefly closed as firefighters responded to the incident.
The PES refining complex -- which has existed in some form for more than 150 years -- is the largest of its kind on the US East Coast, according to its website, and processes 335,000 barrels of crude per day.
PES is a partnership between fuel distributor Sunoco, a subsidiary of Energy Transfer LP, and US-based investment firm The Carlyle Group, according to its website.