People have been advised to avoid the area and keep windows and doors closed.
Pictures show plumes of black smoke billowing and it can be seen from miles away.
The blaze is believed to be at the the old Odeon Cinema/Tokyo Jo’s nightclub.
One local resident said: “I could see it from near The Range (London Road) and there were lots of fire engines on route.”
This is the second fire as a deliberate fire damaged Grade II listed St Joseph’s Orphanage in city centre last weekend.
He wrote: "The recent fires taking place in Preston City Centre are very disturbing suggesting a possible trend. It has been raised by senior members and officers with both fire and police services. We will continue supporting our emergency services to effectively deal with the matter."
Tokyo Jo’s reunion page on Facebook posted: “Shocking scenes on Church Street this evening... the building formerly know as Tokyo Jo's and the Odeon.. is heavily ablaze.
"This is such a sad day ... but the Tokyo Jo's Jubilee Reunion will go ahead as planned... more of a reason to reminisce and celebrate this once iconic club.”
People have reported seeing the fire from miles away and have taken to social media to share shocking pictures and videos of the blaze. A huge police presence is also in attendance at the scene.
More to follow