East Sussex Fire and Rescue Service received the initial alert at 5.03pm regarding the blaze at the former College of the Holy Child Jesus on Magdalen Road in St Leonards.
By 5.30pm, six fire engines were deployed to the site.
A water carrier and officers were also deployed.
A spokesperson for ESFRS has warned people living nearby to keep their doors and windows closed due to the thick black smoke rising from the building.
“Please avoid the area as roads are being closed,” they added.
Police and electricity operator UK Power Networks are also in attendance.
It is believed the fire broke out on the third floor of the former Catholic college, which closed in 1976.
It was later used as a language school before falling into disrepair, although its chapel remains Grade II listed.
As of 9pm, the incident had been scaled down to three fire engines.
“Firefighting continues and steady progress is being made,” ESFRS said.