Alghero was designated as a diocesan seat in 1503 but construction work on the cathedral did not begin until the 1530s. It was not opened until 1593, and not finished and consecrated until 1730. It is the burial site of the Italian-born Duke of Montferrat (1762-1799) and his brother Count of Asti (1766-1802) who died on the island having caught malaria.
The church was originally in Catalan-Gothic style, as can be seen in the five chapels and ambulatory of the presbytery, which also includes the octagonal base of the bell tower. The nave and the two aisles are however in Late Renaissance style. In the 19th century a Neo-Classicalnarthex was added to the façade, which dramatically changed its appearance.