After some restoration work the interior of the cathedral appears very uniform. It consists of two low side aisles and a higher nave, with a barrel vaulted and cross vaulted ceiling. The appearance of the front of the interior is predominantly Romanesque. The chancel and ambulatory are, by contrast, Gothic. In the crossing remains of Romanesque arches can be seen alongside Gothic ones. The eastern limit of the first small church can be recognized by the stone floor in the right ambulatory. The ceiling paintings and the decoration of the chancel as well as one of the two organs are Baroque.
In the Franciscan chapel, on the left next to the entrance, a tiled picture can be seen which shows the saint preaching to the fishes. Also in the chapel is a font, in which St Anthony (to whom the Igreja de Santo António da Sé is dedicated) is supposed to have been baptized in 1195. One of the Baroque nativity scenes created by the well known Machado de Castro, whose works also include the statue of José I on the Praça do Comércio, can be found in the first small chapel on the left. The original event has been moved into the Portugal of the 18th century with the nativity crib framed by depictions of everyday Portuguese life. In accordance with taste of that time the figures in the background have been foreshortened in order to intensify the impression of depth. The scene was made from terracotta and painted.
The tombs of King Afonso IV and his wife Beatrix have been placed at the sides of the santuary, with the main altar in the center and the patriarch's throne visible in the background.
Nine chapels have been incorporated into the ambulatory which was built later. St Vincent's Chapel used to contain the reliquary of St Vincent. Also in the ambulatory are the 14th century sarcophagi of Lopo Fernandes Pacheco and his wife Maria Vilalobos. Pacheco became a follower of King Afonso IV after successfully supporting him in the last battle fought against the Arabs as part of the Reconquista. A further sarcophagus with similar features appears to be the work of the same sculptor; the person depicted has, however, never been identified.
The sacristy includes the silver, mother of pearl-inlaid reliquary of St Vincent positioned on a marble altar. A statue of the saint holding a caravel and a quill stands behind it.