The church of St Paul traces its origins to the 1570s. Although the church of the Dominican fathers had already been declared as parish of Valletta, the Cathedral Chapter insisted on having a church of its own from where to administer sacraments to the inhabitants. Another church was constructed in 1609 but was demolished in 1639. The plans of the new church were prepared by Bartolomeo Garagona. The facade was rebuilt in 1885 to the design of Nicola Zammit.

St Paul is considered to be the spiritual father of the Maltese. His shipwreck is popularly considered as the greatest event in the nation's history. For this reason, St Paul's Collegiate Church is one of the most important in Malta. The church hosts fine artistic works, including the magnificent altarpiece by Matteo Perez d'Aleccio, the choir and dome of Lorenzo Gafa, the paintings by Attilio Palombi, and Giuseppe Cali and the titular statue of Melchiorre Gafa.

One can also view the treasured relic of the right wrist-bone of St Paul, and part of the column on which the saint was beheaded in Rome.