It had originally been proposed that Carlo marry the Pope's niece but he instead suggested it was an ecclesiastic career that he sought.

[2] Barberini was the cardinal deacon of the titulus of San Cesareo in Palatio (18 August 1653),[3] then of S. Angelo in Pescheria (14 November 1667) and finally of S. Maria in Cosmedin (2 December 1675).

He was later promoted to rank of cardinal-priest of the titulus of S. Maria della Pace (27 September 1683).

After becoming protopriest of the Sacred College, he was transferred to the title of S. Lorenzo in Lucina, proper of senior cardinal-priest (30 April 1685).

Carlo Barberini acted in the papal curia as cardinal-protector of the Duchy of Savoy (from 1671), of the Catholic cantons of Switzerland (from 1680) and of the Kingdom of Poland (from 1681).