Born in Plasencia, Ávila y Zúñiga came to the attention of the king of Spain, the Holy Roman Emperor Charles V, serving him as ambassador to Rome. He was made a grand commander of the order of the Knights of Alcantara and accompanied the emperor to Africa in 1541. He also participated with Charles in the war against the Schmalkaldic League, culminating in the Battle of Mühlberg on 24 April 1547.