He received the clerical tonsure and the minor orders on October 20 1689 and was created cardinal deacon in the consistory of November 7 1689, receiving the red hat on November 14. He was superintendent general of the affairs of the Apostolic See, and governor of the cities of Fermo and Tivoli, as well as of the territory of Capranica.
He held the office of vice-chancellor of the Holy Roman Church from November 14 1689 until February 29 1740. He was cardinal-bishop of Sabina 1725, cardinal-bishop of Frascati, 1730, Cardinal-bishop of Porto and Santa Rufina, 1734, and vice-dean then dean of the Sacred College of Cardinals (September 3 1738). Ottoboni was also archpriest of the patriarchal Liberian basilica, secretary of the Roman Inquisition, Archpriest of the patriarchal Lateran basilica (from 1730) and Grand prior of Ireland.
Ottoboni was one of the great patrons of his generation. He resided in the Palazzo della Cancelleria, where he supported Arcangelo Corelli, the finest violinist of his generation, at his Monday night concerts called "academies". Through these concerts, Corelli was introduced to Handel. When he died in 1713, Corelli left his estate, including his valuable pictures, to the Cardinal, who distributed the sizable funds among Corelli's relations and erected a princely tomb for the musician in the Pantheon. Other protegés of the cardinal were Antonio Vivaldi and Antonio Caldara. Ottoboni even wrote texts of cantatas for some of them. When opera was banned in Rome, performances withdrew to Ottoboni's Cancelleria. His triumphal return to Venice in 1726 was celebrated with musical festivities that included a serenata Andromeda liberata, with arias contributed by various Venetian masters, including Vivaldi.
The young Sicilian architect Giovanni Battista Vaccarini and painters Sebastiano Conca, Sebastiano Ricci and Francesco Trevisani also benefited from his patronage. One of his most important commissions were the Seven Sacraments executed in 1712 by Giuseppe Maria Crespi (now in the Museum of Dresden). In 1735 he donated his Roman sculptures and other antiquities to the Capitoline Museums.
His music library was dispersed after his death, but the so-called "Manchester Concerto Part-books" have survived with sets of separate parts for 95 compositions, mostly concertos; the manuscript scores came into the possession of Charles Jennens, the librettist for Handel’s Messiah. The diverse contents of the concerto collection suggest that Ottoboni’s musicians acquired and performed music from artistic centres elsewhere (notably Venice and Bologna) as well as works composed in Rome.
Ottoboni was a member of the Academy of Arcadia.