The fire service was called around 1pm this afternoon.
Pupils and teaching staff have been evacuated from the building, with eyewitnesses saying the roof has collapsed at the school.
A Scottish Fire and Rescue spokeswoman said: "Crews have told us it is a severe fire.
"We have three fire appliances in attendance and two are en-route."
The fire service confirmed that all people in building had been accounted for.
Several emergency vehicles are on the scene.
Parents have been warned to stay away from the school.
Parents can pick up pupils from Priorsford Primary while children taken by bus to the school are going to St Andrew's Parish Church until the end of the school day, a group representing parents and carers at the school posted online.
Conservative MSP for South Scotland Michelle Ballantyne said the fire was "devastating".
She said: "I'm relieved to hear that so far there have been no casualties. My thoughts are with the students and staff and Peebles High School.
"I believe we owe a massive debt of gratitude to our firefighters and emergency workers who are onsite managing the situation.
"This will be heartbreaking for the staff and pupils, and over the next few days I know council officials will be working very hard to ensure pupils' education will not be disrupted."
Shona Haslam, Scottish Borders Council leader, said: "All kids are safe and sound. Parents please don’t try and go to the school. It will restrict access for emergency vehicles. Group call will be used as usual for communication."
Peebles High School Parents & Carers said: "We have been told all students are safe and please- to allow access to the road- would cars stay away from the school."