It was Sarah who persuaded Anne to side with the Protestant ruler William III of Orange, stadholder of the Netherlands, when William overthrew James II in 1688. By the Bill of Rights (1689), William and his wife Mary (Mary II), Anne's elder sister, were made king and queen of England, and Anne was placed in line for the succession to the throne. Anne and Mary had a bitter falling-out, and after Mary's death in 1694 William cultivated Anne's goodwill, but he refused to appoint her regent during his absences from England.

Although Anne was pregnant 18 times between 1683 and 1700, only five children were born alive, and of these, only one, a son, survived infancy. His death in 1700 ended Anne's hopes of providing herself and the three kingdoms (England, Scotland, and Ireland) with a successor. Hence, she acquiesced to the Act of Settlement (Settlement, Act of) of 1701, which designated as her successors the Hanoverian descendants of King James I of England, through his daughter Elizabeth.

Anne became queen upon William's death in March 1702. From the first she was motivated largely by an intense devotion to the Anglican church. She detested Roman Catholics and Dissenters and sympathized with High Church Tories. At the same time, she sought to be free from the domination of the political parties. Her first ministry, though predominantly Tory, was headed by two neutrals, Sidney Godolphin and the Duke of Marlborough. The influence of Sarah Churchill (now Duchess of Marlborough) over Anne was slight after 1703, though the duke remained commander of the British forces.

Anne soon discovered that she disagreed with the Tories on strategy for the war; the queen, Marlborough, and the Whigs wanted to commit English troops to continental campaigns, while the Tories believed England should engage the enemy principally at sea. Consequently, as Marlborough accumulated impressive victories on the Continent, pressure was exerted on Anne to admit Whigs to the ministry. She resisted obstinately and even grew cold toward the duchess, who adopted the cause of the Whig politicians. By 1707 the duchess had been supplanted in the queen's affections by Abigail Masham (Masham, Abigail, Baroness Masham Of Otes), the tool of the leading Tory, Robert Harley (later 1st Earl of Oxford (Oxford, Robert Harley, 1st Earl of, Earl Mortimer, Baron Harley of Wigmore)). Nevertheless, the schemes of Harley and Masham caused Anne so much embarrassment that in 1708 she was forced to dismiss Harley and admit the most prominent Whigs into her administration. As the war dragged on, the nation turned against the Whigs. In 1710 Anne was able to expel them and appoint a Tory ministry. She dismissed both Marlboroughs from her service in 1711.

The queen's advancing age and her infirmities made the succession a crucial issue. Leading Tories were in constant communication with Anne's exiled Roman Catholic half brother, James, the Old Pretender, who had been excluded by law from the succession. Nevertheless, the suddenness of Anne's final illness and death frustrated any plans the Tories might have had for capturing the throne for the Pretender. Her last act was to secure the Protestant succession by placing the lord treasurer's staff in the hands of a capable moderate, Charles Talbot, Duke of Shrewsbury (Shrewsbury, Charles Talbot, duke and 12th earl of, Marquess Of Alton), who presided over the peaceful accession of the Hanoverian prince George Louis (King George I, 1714–27).