On the outbreak of the Civil War, he joined the parliamentary army, fighting at the Battle of Edgehill in October 1642, and at the Battle of Gainsborough in July 1643. He was made deputy-governor of the Isle of Ely by Cromwell and served under Earl of Manchester in the Yorkshire campaign and at the second Battle of Newbury, afterwards supporting Cromwell in his accusations of incompetency against the Earl.

On the night before the Battle of Naseby, in June 1645, Ireton succeeded in surprising the Royalist army and captured many prisoners. The next day, on the suggestion of Cromwell, he was made commissary-general and appointed to the command of the left wing, Cromwell himself commanding the right. The wing under Ireton was completely broken by the impetuous charge of Rupert and Ireton was wounded and taken prisoner, but Cromwell charged and successfully routed the Royalists, freeing prisoners including Ireton.

Ireton was at the siege of Bristol in September 1645 and took part in the subsequent campaign that succeeded in overthrowing the royal cause. On 30 October 1645 Ireton entered parliament as member for Appleby. On 15 June 1646, during the siege of Oxford he married Bridget Cromwell, eldest daughter of Oliver Cromwell. The marriage brought Ireton's career into parallel with Cromwell's.