The blaze broke out shortly after 21:00 BST on Sunday night.
Twenty-two firefighters from Strabane, Londonderry, Castlederg and Newtownstewart fought the flames. The operation ended at midnight.
The building has been "significantly damaged by the fire", said NIFRS western commander Mark Deeney.
There have been a series of arson attacks at the site in recent years, including two fires within the space of two days in June.
The former linen mill dates back to 1835 and was owned by the Herdman family for more than 170 years.
It once employed more than 1,000 people but it closed as a working mill in 2004.
Ten years later, the derelict site was bought by County Tyrone lottery winner Margaret Loughrey from Strabane.
It was reported at the time that she paid Â£1m for the site, just months after she won almost Â£27m in the Euromillions jackpot in December 2013.
A major fire at the derelict Herdman's Mill in Sion Mills was arson, the Northern Ireland Fire and Rescue Service (NIFRS) has said.