The invocation cathedral of Nª Srª da Assunção, was built at the initiative of João III de Portugal in the place where the Church of Santa Maria do Castelo had previously stood. With a design by Afonso Álvares, it was started in 1556. Its last stone, the closing of the vault, was placed in 1571, having been completed and consecrated in the same century.

The project is by Afonso Álvares (act.1550-1575), architect and military engineer at the service of D. João III, author of the cathedral of Leiria (1552), with which that of Portalegre shares similarities.

At the request of D. João III, Pope PaulIII detached Portalegre from the bishopric of Guarda and created the new diocese (1549). The best of the parish churches was chosen to win the title of cathedral, adding the two closest parishes to reinforce resources. The chosen place was the church of Santa Maria do Castelo, as it is the parish with the most customers, but it can also be located in the most noble part of the city.

Its first bishop was Dom Julião. In 1795, as determined by Bishop D. Manuel Tavares, it was restored, dating from its period to its current form. On that occasion, he also expanded the Episcopal Palace, erected his own building for the Registry of the Ecclesiastical House and ordered the construction of the Church of São Tiago. Maria II of Portugal offered the Cathedral of Portalegre a cast bell in Estremoz.

At this time, a "floor" style was adopted, with an austere design with coldly rational interiors and exteriors, well-defined volumes, where there is a certain influence of the robustness and de-tempering of traditional military architecture. It did not fail to incorporate the characteristics of the previous "Manueline" style - such as the ribbed, flattened vaults at the same height (church-hall). What sets this Cathedral apart from the other two cathedrals (Leiria) is its Renaissance dome on the cruise. Its facade is elegant, with volumes protruding from the towers. This cloister was later built between 1726 and 1795, housing some rooms, chapel and cistern.