He entered Trinity College, Oxford, in 1666, but left the university without taking a degree. His first tragedy, Cambyses, King of Persia, was produced at Lincoln's Inn Fields in 1667. The success of this play led the earl of Rochester to encourage the new writer as a rival to Dryden. Through his influence Settle's Empress of Morocco (1671) was twice acted at Whitehall, and proved a signal success on the stage. It is said by Dennis to have been "the first play that was ever sold in England for two shillings, and the first play that was ever printed with cuts." These illustrations represent scenes in the theatre, and make the book very valuable.
The play was printed with a preface to the earl of Norwich, in which Settle described with scorn the effusive dedications of other dramatic poets. Dryden was obviously aimed at, and he co-operated with Crowne and Shadwell in an abusive pamphlet entitled "Notes and Observations on the Empress of Morocco" (1674), to which Settle replied in "Some Notes and Observations on the Empress of Morocco revised" (1674). In the second part of Absalom and Achitophel, in a passage certainly by Dryden's hand, he figures as "Doeg."
Neglected by the court party he took an active share in the anti-popish agitation. When this subsided he turned round to expose Titus Oates, and with the Revolution he veered towards the Whig party. But he had lost the confidence of both sides, and "recanting Settle" accordingly abandoned politics for the appointment (1691) of city poet. In his old age he kept a booth at Bartholomew Fair, where he is said to have played the part of the dragon in a green leather suit devised by himself. He became a poor brother of the Charterhouse, where he died on the 12th of February 1724.
Settle's numerous works include, beside numerous political pamphlets and occasional poems: