He was a relative of Pope Paul IV through whose household he gained preferment in the Roman Curia.
He entered the Roman Curia in 1555 and became a canon of the patriarchal Vatican basilica in 1558.
Pope Pius IV persecuted the family of Carafa and he fled from Rome in 1561.
Pope Pius V rehabilitated the Carafas and Antonio was reappointed to the canonship on 1 June 1566.
After the death of Cardinal Guglielmo Sirleto, he was named Librarian of the Holy Roman Church on 6 October 1585.