Montagu accompanied Prince Charles during his 1623 trip to Habsburg Spain in pursuit of the Spanish Match. He was Member of Parliament for Huntingdonshire in the "Happy Parliament" of 1623-24, the "Useless Parliament" of 1625, and the Parliament of 1625-26. At the time of Charles I's coronation in February 1626, he was made a Knight of the Bath to reward him for his service to Charles in Spain. In May, with help from George Villiers, 1st Duke of Buckingham, Montagu was elevated to the House of Lords, receiving his father's barony of Kimbolton and being styled Viscount Mandeville as a courtesy title, since his father had been created earl of Manchester in February when Parliament convened.
The influence of his father-in-law, who was afterwards admiral on the side of the parliament, drew Mandeville to the popular side in the questions in dispute with the crown, and at the beginning of the Long Parliament he was one of the recognized leaders of the popular party in the Upper House, his name being joined with those of the five members of the House of Commons impeached by the king in 1642. At the outbreak of the Civil War, having succeeded his father in the earldom in November 1642, Manchester commanded a regiment in the army of Robert Devereux, 3rd Earl of Essex, and in August 1643 he was appointed Major-General of the parliamentary forces in the eastern counties, with Cromwell as his second in command. He soon appointed his Provost-Marshall, William Dowsing, as a paid iconoclast, touring the churches of Suffolk and Cambridgeshire destroying all "Popish" and "superstitious" imagery, as well as features such as altar-rails.
Having become a member of the "Committee of Both Kingdoms" in 1644, he was in supreme command at Marston Moor but in the subsequent operations his lack of energy brought him into disagreement with Cromwell, and in November 1644 he strongly expressed his disapproval of continuing the war. Cromwell brought the shortcomings of Manchester before Parliament in the autumn of 1644 and in April the following year, anticipating the Self-denying Ordinance, Manchester resigned his command. He took a leading part in the frequent negotiations for an arrangement with Charles, was custodian with William Lenthall of the Great Seal from 1646 to 1648, and frequently presided in the House of Lords. He opposed the trial of the king, and retired from public life during the Commonwealth but after the Restoration, which he actively assisted, he was loaded with honours by Charles II. In 1667 he was made a General, and he died on May 5, 1671. Manchester was made a Knight of the Order of the Garter in 1661, and became a Fellow of the Royal Society in 1667.
Men of such divergent sympathies as Baxter, Burnet and Clarendon agreed in describing Manchester as a lovable and virtuous man, who loved peace and moderation both in politics and religion. He was five times married, leaving children by two of his wives, and was succeeded in the title by his eldest son, Robert, 3rd Earl of Manchester (1634–1683). One of his daughters went on to become Lady Anne Montagu.