Soon after his accession, the War of Spanish Succession broke out. Despite initially holding an ambiguous neutrality, Clement was later forced to name Charles, Archduke of Austria, as King of Spain, since the imperial army had conquered much of northern Italy and was threatening Rome itself (January 1709).
By the Treaty of Utrecht that concluded the War, the Papal States lost their suzerainty over the Farnese Duchy of Parma and Piacenza in favour of Austria, and lost Comacchio as well. It was a blow from which the declining prestige of the Papal States would never recover.
In 1713 the bull Unigenitus was published. The bull greatly disturbed the peace of the Gallican (French) church. It condemned 101 propositions from the works of Quesnel as heretical and as identical with propositions already condemned in the writings of Jansen.
The resistance of many French ecclesiastics and the refusal of the French parlements to register the bull led to controversies extending through the greater part of the 18th century. Because the local governments did not officially receive the bull, it was not, technically, in force in those areas – an example of the interference of states in religious affairs common before the 20th century.
Another important decision of Clement XI was in regard to the Chinese Rites controversy: the Jesuit missionaries were forbidden to take part in honors paid to Confucius or the ancestors of the Emperors of China, which Clement XI identified as "idolatrous and barbaric", and to accommodate Christian language to pagan ideas under plea of conciliating the heathen.
Clement XI died at Rome in 1721 and was buried in the pavement of St. Peter's Basilica.
As a builder, Clement had a famous sundial added in the church of Santa Maria degli Angeli e dei Martiri and had an obelisk erected in the Piazza del Pantheon and a river port built on the Tiber River.
He established a committee, overseen by his favorite artists, Carlo Maratta and Carlo Fontana, to commission statuary of the apostles to complete the decoration of San Giovanni in Laterano. He also founded a painting and sculpting academy in the Campidoglio.
He also enriched the Vatican library with numerous Oriental codexes and patronaged the first archaeological excavations in the Roman catacombs. In his native Urbino he restored numerous edifices and founded a public library.