When a quarrel broke out between King Charles I and the Parliament, Bedford supported the demands of the House of Commons as embodied in the Petition of Right, and in 1629 was arrested for his share in the circulation of Sir Robert Dudley’s pamphlet, "Proposition for His Majesty’s service," but was quickly released. The Short Parliament meeting in April 1640 found the earl as one of the king’s leading opponents. He was greatly trusted by John Pym and Oliver St John, and is mentioned by Clarendon as among the “great contrivers and designers” in the House of Lords. In July 1640 he was among the peers who wrote to the Scottish leaders refusing to invite a Scottish army into England, but promising to stand by the Scots in all legal and honourable ways. His signature was afterwards forged by Thomas, Viscount Savile, in order to encourage the Scots to invade England. In the following September he was among those peers who urged Charles to call a parliament, to make peace with the Scots, and to dismiss his obnoxious ministers; and was one of the English commissioners appointed to conclude the treaty of Ripon.
When the Long Parliament met in November 1640, Bedford was generally regarded as the leader of the parliamentarians. In February 1641 he was made a privy councillor, and during the course of some negotiations was promised the office of Lord High Treasurer. He was essentially a moderate man, and seemed anxious to settle the question of the royal revenue in a satisfactory manner. He did not wish to alter the government of the church, was on good terms with Archbishop Laud, and, although convinced of the guilt of Strafford, was anxious to save his life. In the midst of the parliamentary struggle Bedford died of smallpox on May 9 1641.
Clarendon described him as "a wise man, and of too great and plentiful a fortune to wish the subversion of the government," and again referring to his death, said that "many who knew him well thought his death not unseasonable as well to his fame as his fortune, and that it rescued him as well from some possible guilt as from those visible misfortunes which men of all conditions have since undergone."
Bedford was the head of those who undertook to drain the great level of The Fens of Cambridgeshire, which were renamed the "Bedford Level" in his honour. He spent a large sum of money over this work, and received 43,000 acres (174 km²) of land. However, owing to various jealousies and difficulties, the king took the work into his own hands in 1638, making a further grant of land to the earl.