Lord Manchester was five times married, leaving children by two of his wives. He married firstly, Susannah Hill on 6 February 1623. She was a daughter of John Hill and Dorothy (née Beaumont) Hill (a daughter of Anthony Beaumont of Glenfield and sister of Mary Villiers, Countess of Buckingham). Through her aunt, Susannah was a first cousin of George Villiers, 1st Duke of Buckingham. They had no children.

He married secondly, 1 July 1625, Lady Anne Rich, daughter of Robert Rich, 2nd Earl of Warwick and the former Frances Hatton (daughter and heiress of Sir William Newport, who later took the surname Hatton to inherit the estates of his uncle, Sir Christopher Hatton). Before her death on 16 February 1642, they were the parents of three children:

  • Robert Montagu, 3rd Earl of Manchester (1634–1682), who married Anne Yelverton, the only daughter of Sir Christopher Yelverton, 1st Baronet.
  • Lady Frances Montagu, who married Henry Saunderson.
  • Lady Anne Montagu (d. 1689), who married her second cousin Robert Rich, 5th Earl of Warwick, the son of Henry Rich, 1st Earl of Holland.

On 20 December 1642, ten months after the death of his second wife, he married her first cousin, Essex, Lady Bevill. She was the widow of Sir Thomas Bevil and a daughter of Sir Thomas Cheek and the former Lady Essex Rich (a daughter of Robert Rich, 1st Earl of Warwick). Before her death on 28 September 1658, they had a daughter:

  • Lady Essex Montagu (d. 1677), who married Henry Ingram, 1st Viscount of Irvine in 1661.

In July 1659, Lord Manchester married Eleanor, Dowager Countess of Warwick, as his fourth wife. Eleanor, who had been his second wife's stepmother, was a daughter of Sir Richard Wortley and sister of Sir Francis Wortley, 1st Baronet. At the time of their wedding, she had been thrice widowed, first from Sir Henry Lee, 1st Baronet, then Edward Radclyffe, 6th Earl of Sussex and, lastly, of Robert Rich, 2nd Earl of Warwick. The Earl and Countess Eleanor had no children together.

After his fourth wife's death in 1666, Lord Manchester was married for a fifth, and final, time to Margaret, Dowager Countess of Carlisle on 31 July 1667. Margaret, a widow of James Hay, 2nd Earl of Carlisle, was the third daughter of Francis Russell, 4th Earl of Bedford and the Hon. Katharine Brydges (second daughter and co-heiress of Giles Brydges, 3rd Baron Chandos). She survived him and died in 1676.