Pablo was born and brought up in the house of his father's maternal uncle, Francisco Lopez de Aponte, Canon of Cordoba, where he received a learned education.
At the age of eighteen, in 1556, he was sent to the Universidad Complutense in Alcalá de Henares, and there, devoted himself to the acquirement of Oriental languages and theology.
He was in Rome in February 1559, engaged in conducting certain negotiations for the Archbishop Carranza de Miranda, of Toledo, who then stood charged with heresy before the Inquisition of Valladolid.
His only surviving works from that period are the frescoes he painted in the Bonfili chapel at the Santa Trinità dei Monti church in Rome.
In 1604 he composed his Discourse of Ancient and Modern Painting and Sculpture in which he recounts anecdotes of Renaissance masters of Italy.