He was knighted at his father's coronation on the 11th of October 1399, and created duke of Gloucester by Henry V at Leicester on the 16th of May 1414. He served in the war next year, and was wounded at Agincourt, where he owed his life to his brother's valour. In April 1416 Humphrey received the emperor Sigismund at Dover and, according to a 16th-century story, did not let him land till he had disclaimed all title to imperial authority in England. In the second invasion of France Humphrey commanded the force which during 1418 reduced the Cotentin and captured Cherbourg. Afterwards he joined the main army before Rouen, and took part in subsequent campaigns till January 1420. He then went home to replace Bedford as regent in England, and held office till Henry's own return in February 1421. He was again regent for his brother from May to September 1422.
Henry V measured Humphrey's capacity, and by his will named him merely deputy for Bedford in England. Humphrey at once claimed the full position of regent, but the parliament and council allowed him only the title of protector during Bedford's absence, with limited powers. His lack of discretion soon justified this caution.
Bedford, in the interest of so important an ally, endeavoured vainly to restrain his brother. Finally in October 1424 Humphrey took up arms in his wife's behalf, but after a short campaign in Hainault went home, and left Jacqueline to be overwhelmed by Burgundy. Returning to England in April 1425 he soon entangled himself in a quarrel with the council and his unde Henry Beaufort, and stirred up a tumult in London. Open war was averted only by Beaufort's prudence, and Bedford's hurried return. Humphreyhad charged his uncle with disloyalty to the late and present kings. With some difficulty Bedford effected a formal reconciliation at Leicester in March 1426, and forced Humphrey to accept Beaufort's disavowal. When Bedford left England next year Humphrey renewed his intrigues. But one complication was removed by the annulling in 1428 of his marriage with Jacqueline. His open adultery with his mistress, Eleanor Cobham, also made him unpopular. To check his indiscretion the council, in November 1429, had the king crowned, and so put an end to Humphrey's protectorate. However, when Henry VI was soon afterwards taken to be crowned in France, Humphrey was made lieutenant and warden of the kingdom, and thus ruled England for nearly two years. His jealousy of Bedford and Beaufort still continued, and when the former died in 1435 there was no one to whom he would defer. The defection of Burgundy roused English feeling, and Humphrey won popularity as leader of the war party. In 1436 he commanded in a short invasion of Flanders. But he had no real power, and his political importance lay in his persistent opposition to Beaufort and the councillors of his party. In 1439 he renewed his charges against his uncle without effect.
In 1441 Eleanor was charged with practising sorcery against the king, and Humphrey had to submit to see her condemned, and her accomplices executed. Nevertheless, he continued his political opposition, and endeavoured to thwart Suffolk, who was now taking Beaufort's place in the council, by opposing the king's marriage to Margaret of Anjou. Under Suffolk's influence Henry VI grew to distrust his uncle altogether. The crisis came in the parliament of Bury St Edmunds in February 1447. Immediately on his arrival there Humphrey was arrested, and four days later, on the 23rd of February, he died. Rumour attributed his death to foul play. But his health had been long undermined by excesses, and his end was probably only hastened by the shock of his arrest. Humphrey was buried at St Albans Abbey, in a fine tomb, which still exists.
He was ambitious and self-seeking, but unstable and unprincipled, and, lacking the fine qualities of his brothers, excelled neither in war nor in peace. Still he was a cultured and courtly prince, who could win popularity.
In the autumn of 1422 he married Jacqueline of Bavaria, heiress of Holland, to whose lands Philip of Burgundy had claims.
Later he married Eleanor Cobham.