Northern Ireland Fire and Rescue Service has sent 11 appliances to the scene in the Castle Street district of the city.
There are no reports of any injuries, but the public has been advised to avoid the area while the incident is ongoing.
According to local councillor Julie-Anne Corr-Johnston, the store had only recently been refurbished.
She tweeted: “The Primark building in Belfast City Centre has caught fire. Emergency services are responding.
“Devastating news particularly following the recent refurbishments and extension.”
Smoke can be seen billowing from the building from across the city, with police advising that multiple traffic diversions are in place.
Motorists are asked not to use Bridge Street, High Street, Castle Street, Queens Street, Royal Avenue and North Street to allow fire crews to deal with the blaze.