The fire started in a bedroom of the property in Chappaqua, New York.
New Castle police confirmed the blaze started at the Clinton property.
Fire crews said the blaze was on the second floor of a building, thought to be a guest house rather than the main structure.
Sergeant Arthur Mendoza of the New Castle Police Department said the fire was under control by 3.15pm local time.
It is unknown if anyone was at home at the time of the blaze.
The pair bought the huge building for $1.7m back in 1999 and have lived there ever since.
In 2016, they bought the mansion next door, bringing the two buildings together into one compound.
The original building has 11 rooms and was built at the start of the 20th century.
Mrs Clinton wrote parts of her memoir What Happened at the building and has spent much of the past few months publicising the book around the world.
More to follow.