While still a teenager he was granted several ecclesiastical benefices, including the parish of Santa María in the town of Hita and the archdeacon of Guadalajara.

When the archbishop died in 1446, he moved to the University of Salamanca, where he studied civil and canon law and earned doctorates in both by 1452.

As a result of his influential family and status as chaplain to the king, Mendoza was soon appointed to his first bishopric: in 1453 he was selected by Juan II to become Bishop of Calahorra.

The pope later confirmed his election and Mendoza was consecrated in 1454 by Alfonso Carrillo de Acuña, the Archbishop of Toledo.

he was the partisan of the Princess Isabella, afterwards queen, while his eldest brother Diego Hurtado de Mendoza, 2nd marquis of Santillana, remained however faithful to king Henry IV of Castile, till his death in December 1474.

[citation needed] Pedro, the cadet brother, fought for her at the Battle of Toro on 1 March 1476, when King Henry IV had died already.

Though his life was worldly, and though he was more soldier and statesman than priest, the "Great Cardinal", as he was commonly called, did not neglect his duty as a bishop.

It is said that he recommended her to choose as his successor the Franciscan Jimenez de Cisneros, a man who had no likeness to himself save in political faculty and devotion to the authority of the Crown.