Crews from The Mounts, Mereway, Moulton, Earls Barton and Brixworth were called to a fire in the fourth floor of the building at around 9pm and closed off College Street to the rear of the site to deal with the blaze.
There are no reports yet of injuries nor the extent of damage to the building.
Police have confirmed two boys aged 14 and 17 were arrested in connection with the incident and others in the town centre
Debenhams closed its doors in the Drapery in May 2021 after the iconic retailer was liquidated, ending nearly 70 years of trading in Northampton.
The site has been earmarked for redevelopment to be replaced by a mixed-use building including a smaller retail unit, more than 200 flats, gym and central courtyard.