Dedicated to the Patron Saint of the Order of the Knights of St. John, the church was given Co-Cathedral status with the Mdina Cathedral in 1882. Before it was built, the knights’ Conventual church was located at Birgu. Building of St. John’s Co-Cathedral started in 1573 under Grand Master La Cassière who paid for the initial cost. The architect was Girolamo Cassar. It was solemnly blessed by Bishop Ludovik de Torres in 1578.
The church was administered by a chapter of ‘cappellani maggiori’ all of whom were ordained members of the Order of St. John. The church has a central nave with chapels on each of two side aisles, each chapel corresponding to a Langue of the Order, namely: Auvergne, Aragon, Castile, Leon & Portugal, Anglo-Bavaria, Provence, France, Italy, Germany and the Chapel of Our Lady of Philermos.
The floor consists of 400 ornate marble gravestones over the graves of the knights who died in Malta. In the crypt lie the remains of several grandmasters in ornate graves.