Lisle was elected Member of Parliament for Winchester during the Short and Long Parliaments and was active on the Hampshire county committee during the First Civil War. In the Parliament of England, he was chairman of the committee that investigated Oliver Cromwell's allegations against the Earl of Manchester in December 1644. He also chaired the committee that framed the ordinance to create the New Model Army early in 1645. Lisle voted against continuing negotiations with the King after the Second Civil War (1648) and was appointed a commissioner of the High Court of Justice for the King's trial in January 1649. He sat beside Lord-President John Bradshaw during the trial to advise him on points of law. He also helped to draw up the sentence, but he was not a signatory of the King's death warrant. With the establishment of the Commonwealth of England, Lisle was one of the commissioners who framed the new republican constitution. He sat on the five-man committee appointed to select members of the Council of State, and in February 1649 he was made a commissioner of the Great Seal. Lisle was active as a law reformer, but he also gained a reputation for acquisitiveness and sharp practice.
Lisle continued to hold high office after Cromwell's dissolution of the Rump Parliament in April 1653, and administered the oath of office when Cromwell became Lord Protector. He supported the offer of the Crown to Cromwell and was appointed to the controversial Upper House in December 1657. When the Rump was restored in May 1659, Lisle was dismissed from most of his lucrative offices. He escaped abroad at the Restoration and settled at Lausanne in Switzerland with other exiled republicans. In August 1664, as he was leaving the church at Lausanne, Lisle was shot and killed by an Irish Royalist known as Thomas MacDonnel.