The main building at Cherwell Valley Services is understood to have been completely destroyed by fire.
More than a dozen crews are currently battling the blaze at Junction 10 of the M40, near Bicester.
The fire started in the roof space of the buildings shortly before 1pm, the fire service said.
Crews are currently trying to stop the blaze spreading to the neighbouring Travelodge.
The petrol station is not believed to be under threat.
Police said they would close the M40 if the smoke dropped over the road.
The services are completely shut and all buildings have been evacuated. No one is believed to have been hurt.