In 1661, aged thirty-five, he was created Cardinal-Priest of Sainte Balbine by Pope Alexander VII.

[1] In 1666, he was replaced by his brother, Pedro Antonio de Aragón, as he was called back to Spain to become Archbishop of Toledo.

Aragón had enjoyed the patronage of the previous Archbishop, Baltasar Moscoso y Sandoval, and upon the latter's death in 1665 had been nominated to succeed him.

In 1665, King Philip IV had died as well, leaving the throne to his son Charles II, a weak four-year-old.

When Queen Mariana of Austria promoted her confessor and former tutor, the Austrian Jesuit Juan Everardo Nithard to the position of General Inquisitor in 1666 and thus admitted him to the council, Archbishop Aragón was among those who antagonised him and in 1669 supported John of Austria's military pronunciamiento, which resulted in the Jesuit's dismissal.