Shortly after 01:00, Greater Manchester Fire and Rescue Service received reports of a fire involving the first and second floors of a disused terraced building opposite Brideoak Street.
Crews from Manchester Central and Broughton Fire Stations were initially sent to the scene but extra crews were then drafted in.
Around 25 firefighters and two aerial platforms, plus a specialist command vehicle, were sent to fight the blaze which had spread to two adjoining properties via the roof space.
The fire had spread to three shops which are believed to be a wedding shop, an alternative therapy business and a bookkeeping premises which suffered some smoke and water damage.
Cheetham Hill Road is expected to remain closed for most of the day.