He began his career as a monk of the Order of Saint Jerome, was appointed the queen's confessor and with her support and patronage, became the Archbishop of Granada.

He was also a long-time opponent of the Spanish Inquisition, a position that ultimately led to his denouncement and arrest by the Inquisitor Diego Rodríguez de Lucero.

In 1470 he was appointed prior of the Monastery of Nuestra Señora del Prado in Valladolid,[3] where he developed extensive reforms for the order.

More than just an Advent sermon, it was both an inspirational spiritual tract and a politically astute guide that had a lifelong influence on queen's approach to her reign.

[9] After the conquest of Granada in 1492, the rights of the Muslim majority to practice their religion was guaranteed in the terms of surrender set forth by Spain.

However, it also marked a turning point in his influence at court when Francisco Jiménez de Cisneros was named to replace him as Isabel's confessor.

Overriding Talavera's objections, his actions incited a revolt which threatened Cisneros' life and was only quashed by the timely intervention of royal forces.

Isabel decided that a peaceful solution was not possible and in February 1502, she issued an edict requiring all adult Muslims in Castile to convert to Christianity or face expulsion.

After the death of his protector Queen Isabel in 1504, he was denounced by the notorious Inquisitor Diego Rodríguez de Lucero and accused of establishing a synagogue in his palace where he conducted Jewish ceremonies with family and other clerics.

The papal nuncio Giovanni Ruffo appealed to Pope Julius II who cleared Talavera of all charges and ordered him released.