Barberini entered the Roman prelature and was named domestic prelate to the Pope in 1820.

In 1823 he was appointed Prefect of the Household of His Holiness, a post he occupied for the next five years.

Barberini was elevated to cardinal (in pectore) in 1826 but was not revealed as such until 1828 He was appointed Prefect of the Sacred Consulta of Ecclesiastical Immunity in 1834, a position he occupied until his death.

In 1862 he was appointed both Secretary of Apostolic Briefs and Grand Chancellor of the Pontifical Equestrian Orders.

Pope Pius IX participated in his funeral and he was buried in his family's chapel in the church of Sant'Andrea della Valle.