Several fire appliances were called to the scene at Carnsalloch House to tackle the blaze.
One witness reported damage to the main part of the house at Kirkton, with floors and the roof burnt out.
The category A listed building had fallen into a state of disrepair and had been described as a target for vandals, fireraisers and drug-users.
The mansion house at Kirkton was built in the middle of the 18th Century, with a number of extensions added over the years.
From the late 1960s until about 2000 it was owned by the Leonard Cheshire foundation.
Plans for a housing development at the site were rejected and earlier this month the developers sought a council review of the decision.
A derelict historic house near Dumfries has been damaged in a fire which broke out overnight on Friday.