The driver of the rig was killed in the incident, Frederick County Fire Chief Tom Coe said at a press conference.
A call to the 9-1-1 center about a house fire on Schley Avenue adjacent to the highway at noon was followed by multiple calls about a tanker explosion, Coe said.
Frederick County firefighters quickly determined that in addition to the tanker, three houses and three vehicles were burning as well as brush as the burning fuel continued to spread.
One house on Apple Avenue sustained extensive damage while two others suffered superficial damage. No civilians were injured.
"Those fires were placed under control within 40 minutes of the dispatch time," the chief said.
Dark smoke from the burning fuel and tanker were visible for many miles in the Frederick area. The highway was shut down for several hours as firefighters worked to control the blaze.
Hazmat crews, assisted by the Maryland Department of the Environment and Frederick Department of Public Works, contained the runoff fuel and prevented it from entering Carroll Creek which flows through downtown Frederick.
Coe added that the foam used to extinguish the massive blaze did not contain PFAS, linked to cancer.
He added that the foam residue visible posed no risk to the public.
More than 100 firefighters responded to the incident including crews from Carroll, Washington, Montgomery and Viriginia as well as Fort Detrick and Camp David.
Frederick Mayor Michael O'Connor called it a 'very scary day' with many moving parts but said the "agencies represent the best what this county does when faced with a tragedy and challenge..."
The mayor went on to thank the responders for their quick actions and coordination which helped control the situation.
There was no spillage into the city's sanitary sewage system. "The city will continue to monitor the environmental effects of this incident."
The Maryland State Police is handling the crash investigation, which is continuing.
The northbound lane of the highway was reopened at 10:51 p.m.