He was born Michelangelo Conti in Poli, near Rome. Like Pope Innocent III (1198–1216), Pope Gregory IX (1227–1241) and Pope Alexander IV (1254-1261), he was a member of the family of the Conti, counts and dukes of Segni. He included the family crest in his Pontifical coats of arms.
He became Cardinal-Priest of Santi Quirico e Giulitta under Pope Clement XI (1700–21) in 1706. From 1697 to 1710 he acted as papal nuncio to the Kingdom of Portugal, where he is believed to have formed those unfavourable impressions of the Jesuits which afterwards influenced his conduct towards them. In 1721 his high reputation for ability, learning, purity, and a kindly disposition secured his election to succeed Clement XI as Pope Innocent XIII. His pontificate was prosperous, but comparatively uneventful. Innocent XIII prohibited the Jesuits from prosecuting their mission in China, and ordered that no new members should be received into the order. This indication of his sympathies encouraged some French bishops to approach him with a petition for the recall of the bull Unigenitus by which Jansenism had been condemned; the request, however, was peremptorily denied.
Innocent XIII, like his predecessor, showed much favour to James Francis Edward Stuart, the "Old Pretender" to the British throne and liberally supported him. The Pope's cousin, Francesco Maria Conti, from Siena, became chamberlain of James' little court in the Roman Muti Palace.