He was elevated to cardinal on 30 August 1627 by Barberini Pope Urban VIII (the uncle of his brother-in-law Taddeo) at the insistence of his sister, Anna.

He celebrated the wedding between Emperor Leopold I and Infanta Margarita of Spain (daughter of Philip IV) and as legate accompanied her to Germany.

Mazarin later assisted Colonna's brother-in-law Taddeo and his brothers when they went into exile during the short schism between the Barberini and the Pamphili.

At the death of the King, Colonna returned to his native Italy but died on 4 September 1666 at the Dominican convent in Finale Marina, near Genoa.

After six years, his remains were moved to Rome and buried in the chapel of his family in the patriarchal Lateran basilica.