Flames broke out in the former Zanzibar nightclub and the Bethel Community Church next door around 6.19pm on Friday evening.
Nearby homes had to be evacuated, and officials warned other residents to stay inside and keep their windows closed.
More than 70 firefighters using 10 fire engines and 11 supporting appliances, including a crane, have been at the scene to attempt to bring the blaze under control.
Images showed major damage to the roof of the church as flames engulfed the inside of the building.
Around 8.10pm there was a large “explosion” in the church, according to witnesses.
WalesOnline reported members of the congregation watched on in horror, crying as they saw the fire’s impact.
One member reported arriving at the building to set up the youth club shortly before the fire took hold.
The church was 140 years old, and the congregation had been raising £183,500 to repair the roof and create a new floor in the upper area.
Paster Andrew Cleverley told WalesOnline: “We were in the process of redeveloping it all and now it’s gone.
“The inside of the roof was quite unique. It was all wood.”
Jennie Griffiths, joint head of South Wales Fire and Rescue Service, said the structural integrity of the building was being assessed.
Social media reports indicted the flames were dying down by 9.30pm.