More than 75 firefighters are tackling the blaze at Selsey Academy in School Lane. Plumes of black smoke can be seen coming from the site.
The blaze broke out about 08:00 BST, with more than 60 calls being made to Sussex Control Centre.
The fire could be seen clearly from Selsey Football Club, which was tweeting footage of the flames.
People in the vicinity are advised to stay clear of the smoke, remain inside and keep their windows closed, but crowds have gathered to watch the firefighting effort.
One resident, whose house overlooks the school, said she saw "plumes and plumes of black smoke towering above the house, rather like an apocalypse".
Hampshire Fire and Rescue Service has sent crews to help West Sussex colleagues.
South East Coast Ambulance Service is also at the scene.
Chairman of governors Bill Emerson said the school was devastated.
"There is a possibility we might be able to save a small section of the school and the emergency services are doing their best to do that," he said.
"But it is amazing how quickly the fire has spread.
"It's shocking. The structures are effectively a skeleton now compared to what they were and we have still got fire raging in sections."
He said it was too early to say what started the blaze.
He added: "It's the only secondary school in the peninsular and it is going to be devastating to the community.
"There are contingency plans in place to make sure the children can pick up their GCSE results [on Thursday] and to make sure we can provide education to children when they start the school year."
Explosions were heard at the scene of a fire that has reduced a secondary school in West Sussex to a skeleton.