Brandon took part in the jousts which celebrated the marriage of Mary Tudor, Henry's sister, with Louis XII of France. He was accredited to negotiate various matters with Louis, and on his death was sent to congratulate the new king Francis I. An affection between Suffolk and the dowager queen Mary had subsisted before her marriage, and Francis roundly charged him with an intention to marry her. Francis, perhaps in the hope of Queen Claude's death, had himself been one of her suitors in the first week of her widowhood, and Mary asserted that she had given him her confidence to avoid his importunities. Francis and Henry both professed a friendly attitude towards the marriage of the lovers, but Suffolk had many political enemies, and Mary feared that she might again be sacrificed to political considerations. The truth was that Henry was anxious to obtain from Francis the gold plate and jewels which had been given or promised to the queen by Louis in addition to the reimbursement of the expenses of her marriage with the king; and he practically made his acquiescence in Suffolk's suit dependent on his obtaining them. The pair cut short the difficulties by a private marriage, which Suffolk announced to Wolsey, who had been their fast friend, on 5 March. Suffolk was only saved from Henry's anger by Wolsey, and the pair eventually agreed to pay to Henry £24,000 in yearly instalments of £1000, and the whole of Mary's dowry from Louis of £200,000, together with her plate and jewels. They were openly married at Greenwich on 13 May. The Duke had been twice married already, to Margaret Mortimer and to Anne Browne, to whom he had been betrothed before his marriage with Margaret Mortimer. Anne Browne died in 1511, but Margaret Mortimer, from whom he had obtained a divorce on the ground of consanguinity, was still living. He secured in 1528 a bull from Pope Clement II. assuring the legitimacy of his marriage with Mary Tudor, and of the daughters of Anne Browne, one of whom, Anne, was sent to the court of Margaret of Savoy. After his marriage with Mary, Suffolk lived for some years in retirement, but he was present at the Field of the Cloth of Gold in 1520, and in 1523 he was sent to Calais to command the English troops there. He invaded France in company with Count de Buren, who was at the head of the Flemish troops, and laid waste the north of France, but disbanded his troops at the approach of winter. Suffolk was entirely in favour of Henry's divorce from Catherine of Aragon, and in spite of his obligations to Wolsey he did not scruple to attack him when his fall was imminent. The cardinal, who was acquainted with Suffolk's private history, reminded him of his ingratitude: " If I, simple cardinal, had not been, you should have had at this present no head upon your shoulders wherein you should have had a tongue to make any such report in despite of us. " After Wolsey's disgrace Suffolk's influence increased daily. He was sent with the Thomas Howard, 3rd Duke of Norfolk to demand the great seal from Wolsey; the same noblemen conveyed the news of Anne Boleyn's marriage to Queen Catherine, and Suffolk acted as High Steward at the new queen's coronation. He was one of the commissioners appointed by Henry to dismiss Catherine's household, a task which he found distasteful. He supported Henry's ecclesiastical policy, receiving a large share of the plunder after the suppression of the monasteries. In 1544 he was for the second time in command of an English army for the invasion of France. He died at Guildford on 24 August in the following year.
After the death of Mary Tudor on 24 June 1533 he had married in 1534 his ward Catherine (1520-1580), suo jure Baroness Willoughby de Eresby, then a girl of fifteen. His daughters by his marriage with Anne Browne were Anne, who married firstly Edward Grey, Lord Powys, and, after the dissolution of this union Randal Harworth; and Mary (b. 1510), who married Thomas Stanley, Lord Monteagle. By Mary Tudor he had Henry, Earl of Lincoln (1516-1534); Frances, who married Henry Grey, Marquess of Dorset, and became the mother of Lady Jane Grey; and Eleanor, who married Henry Clifford, 2nd Earl of Cumberland. By Katherine Willoughby he had two sons who showed great promise, Henry (1535-1551) and Charles (c. 1537-1551), Dukes of Suffolk. They died of the sweating sickness within an hour of one another.