Large sections of Deniliquin High School have been destroyed by fire after a blaze that began in the early hours of Saturday morning required more than three hours to bring under control, with specialist fire investigators now examining the scene.

The fire started about 12.40am in the two-storey building on Harfleur Street, first engulfing classrooms used for metalwork and woodwork before spreading to the library and causing major damage, according to Fire and Rescue NSW Superintendent Stewart Alexander.

Fire and Rescue NSW trucks from Deniliquin, Finley, Moama, Tocumwal and Jerilderie attended the incident, along with a specialist truck from Albury, as well as Rural Fire Service crews, police and ambulance. An estimated 50 firefighters were at the scene at the peak of the blaze.

The most visible damage is to the building at the corner of Wellington and Henry streets, with the Henry Street corridor and sections wrapping around to the school oval visibly gutted by flames. The affected areas traditionally house classrooms for mathematics, design and technology, science and English, as well as the high school library.

Superintendent Alexander said access proved difficult and dangerous for firefighters. Strong winds hampered efforts throughout the morning, with crews hoping to deploy a drone for aerial assessment once conditions eased.

Nearby residents reported hearing loud bangs as the fire was at its worst, with flames leaping high into the air as the blaze took hold.

NSW Police from Murray River Police District have established a crime scene, with specialist fire investigators travelling from Sydney to assess the cause. Superintendent Alexander said the level of damage made determining the cause very difficult. Anyone with information is urged to contact Crime Stoppers on 1800 333 000.

In a social media post on Saturday morning, Deniliquin High School staff expressed their sadness. "We are deeply saddened by the catastrophic fire at school overnight," the post read. "As we know more, we will communicate with our school community. We thank the many firefighters, emergency services, police and ambulance personnel who assisted on site."

The school, which has approximately 450 students from Year 7 to Year 12, faces a significant rebuilding task ahead.