At the start of the war he commanded a foot regiment in the earl of Essex's army, but in August 1643 he was appointed commander of the forces of the Eastern Association, with the support of Cromwell, who was to become his chief rival. As commander of the eastern association he secured Lincolnshire, winning the battle of Winceby (11 October 1643), often considered to be Cromwell's battle, but in reality Manchester and Fairfax's, and captured Lincoln on 6 May 1644. Lincolnshire secure, on 3 June he joined the siege of York, and was present at the battle of Marston Moor (2 July 1644). Although he played no major part in the battle, his regiment remained on the field for the entire battle, with Manchester in personal command for most of the time. By now his relationship with Cromwell had turned sour. Manchester was essentially conservative, while Cromwell was increasingly obviously not. After Essex's defeat in Cornwall, Manchester was ordered to move his army south to aid Waller, but instead he and Cromwell ended up in London, having a blazing row in front of the Committee of Both Kingdoms, while the army of the Eastern Association split into hostile factions.
When the Parliamentary armies came together before the Second Battle of Newbury (27 October 1644), Manchester was the senior general. Success of the plan adopted - a flanking march by Waller with much of the army, required Manchester to attack at the same time as Waller, but Manchester did not move until 4 p.m., one hour after Waller, and only 30 minutes before sunset. Fighting ended before the battle was won, and Charles was able to escape with much of his army. The aftermath of the battle saw Manchester's conduct come under attack from Cromwell and the Independents. The end result of the inquest that followed was the formation of the New Model Army, and the Self Denying Ordinance, which forbade members of either the Commons or the Lords from commanding Parliamentary armies. This was in effect an attack on Essex and Manchester, for while Cromwell and his fellow MP's could resign, that option was not open to the Lords. In the event, Cromwell remained in command and in the commons, but Manchester resigned on 2 April 1645. Whatever the motives behind the Ordinance, the removal of Manchester undoubtedly improved the quality of leadership in Parliament's armies.
Manchester hated the nature of Parliament's peace. He opposed the trial and execution of Charles I, and retired into private life once it was clear that a republic would follow. Like many Parliamentary commanders, he welcomed the return of Charles II, who he served as chancellor, privy councillor and lord chamberlain, even returning to military service in 1667 during the Second Anglo-Dutch War.