More than 30 firefighters, including specialist crews from the ACT, were called out to the blaze about 9.30pm on Friday.

A Bronto unit from ACT Fire and Rescue was dispatched to put out the fire from above, with parts of the building in danger of collapsing.

The blaze was brought under control just before 11pm, with it being totally put out by 2am.

Fire and Rescue NSW zone commander Steven Hayes said ACT crews were called to fight the blaze as other crews were unable to get inside the building.

"We couldn't get access to the building even after the fire because of the damage," he said.

"Crews had to adopt a defensive position."

Southern Highlands Fire Brigade duty commander Aan Gerrard said the historic orphanage had been "completely gutted" and would most likely be pulled down.

Friday night's fire came as part of the building's roof collapsed after a blaze on Thursday, whihc ACT crews had also been called to help fight.

It was the third fire at the site in the last three weeks. A fire had damaged a rear hall on October 17.

Goulburn police are now investigating the cause of the blaze and are treating it as suspicious.

Inspector Rob Post told The Goulburn Post that officers were investigating links between all three fires.

"Police have also been liaising with [Goulburn Mulwaree] Council regarding the integrity of the structure as it remains," he said.

The orphanage was opened in 1912 and had as many as 200 children living at the site before it was decommissioned in 1978.

More recently, the abandoned site was purchased by Goulburn Airport owner John Ferrara.

Mr Ferrara had lodged several development applications for residential developments at the site and also applied for subdivision to build 11 units.

Goulburn mayor Bob Kirk said on Saturday that securing the historic site was a matter of urgency.

with Louise Thrower