The first construction of the cathedral replacing the small church commenced in 1666 under Juan de Medina, and a bell tower was added.

[5] At 4 pm on Holy Thursday, 26 March 1812, an earthquake measuring 7.7 magnitude on the Richter scale struck Caracas.

The priests explained it as divine retribution for Francisco de Miranda's rebellion and the devout parishioners agreed with them even though Simón Bolívar told the people not to panic as it was merely an earthquake.

The cathedral houses crypt chambers, the most notable of which is the Bolívars', as his parents and young bride are entombed here.

In 1974, the cathedral parish's marriage registry for the period 1615–1831 was published by the Instituto Venezolano de Genealogia.

[9] The Romanesque plan consists of five naves: a central one and two minor ones on each side which makes the interior look wide.

[12] The sacral art in the cathedral contains among others The Resurrection by Rubens, the Presentation of the Virgin by Murillo, and the Last Supper, an unfinished work by the Venezuelan painter Arturo Michelena.

[5] Notable figures in the cathedral's history include the isleño Manuel de Sosa Betancourt, who was its archdeacon.