The terrorist group swept into Mosul and proclaimed the city its "capital" in 2014, in an onslaught that forced hundreds of thousands of Christians in the northern Nineveh province to flee, some to Iraq's nearby Kurdistan region.
The Iraqi army drove out the extremist group three years later after months of gruelling street fighting that devastated the city.
The Mar Tuma Syriac Catholic Church, which dates back to the 19th century, was used by ISIS as a prison or a court.
Restoration work is continuing and its marble floor has been dismantled to be completely redone.
In September, a new bell was inaugurated at the church during a ceremony attended by dozens of worshippers.
The 285-kilogram bell cast in Lebanon rang out on Saturday to cries of joy before the Mass got under way.
The service began with worshippers who packed the church chanting hymns as an organist played.
"This is the most beautiful church in Iraq," said Father Pios Affas, 82, the delighted parish priest.
Father Affas also paid tribute to those behind the restoration work which, he said, had "brought the church back to its past glory, like the way it was 160 years ago".
Inside the church, ochre and grey marble shone in the nave, where the altar and colonnaded arches were restored and new stained glass installed.
ISIS had destroyed all Christian symbols, including the holy cross, and parts of the church were damaged by fire and shelling.
Artisans worked diligently to "clean the scorched marble" and restore it, Fraternity in Iraq, a French NGO that aids religious minorities and which helped fund the restoration, said this year.
Outbuildings and rooms on the first floor, where windows have been broken and ISIS graffiti can be seen, are due to be repaired.
Mosul and the surrounding plains of Nineveh were once home to one of the region's oldest Christian communities.
Iraq's Christian population has shrunk from about 1.5 million before the 2003 US-led invasion that toppled dictator Saddam Hussein to fewer than 400,000.
Nineveh was left in ruins after three years of ISIS occupation, which ended in 2017 when Iraqi forces backed by US-led coalition air strikes pushed them out.
Several monasteries and churches are being renovated but reconstruction is slow and the Christian population that has fled has not returned.
In 2018, the UAE teamed up with United Nation’s cultural agency Unesco to rebuild the Al Tahera Church in Mosul as part of its support for post-ISIS reconstruction in the city. The project was later expanded to include the restoration of Al Saa’a Church.
Pope Francis made a historic visit to the region last year in a show of support for Iraq's Christian population.
With reporting from AFP