The fire service said no-one was thought to be inside the building – but warned they expected it to be badly damaged.
Fire service area manager Warren Pickstone said: “We are doing everything we can to save as much of this building as we can. The fire is in the roof and is difficult to access but we have specialist resources at the scene and we are doing our best.
“The fire is in the main black and white traditionally-clad Tudor building with the historic clock tower, which was also on fire.
Wythenshawe Hall, set in 250 acres now known as Wythenshawe Park, was home to the Tatton family for almost 400 years.
It was built in about 1540 and was unsuccessfully defended by Robert Tatton against Oliver Cromwell’s forces in 1643, during the English Civil War
It was donated to local people in 1930 was a museum and art gallery in recent years until it was closed in 2010 by Manchester City Council.
It reopened to visitors in 2012 with help from the Friends of Wythenshawe Hall volunteer group.
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