Humphrey was born on 3rd October 1390  was the fourth son of King Henry IV of England by his first wife, Mary de Bohun.

The place of his birth is unknown, but he was named after his maternal grandfather, Humphrey de Bohun, 7th Earl of Hereford. He was created Duke of Gloucester in 1414, and upon the death of his brother, King Henry V of England in 1422, became regent of the kingdom and protector to his young nephew, King Henry VI.

In about 1422 he married Jacqueline, Countess of Hainaut and Holland, daughter of William VI. Through this marriage Gloucester assumed the title "Count of Holland, Zeeland and Hainault", and briefly fought to retain these titles when they were contested by Jacqueline's cousin Philip III, Duke of Burgundy. They had a stillborn child in 1424.

The marriage was annulled in 1428, and Jacqueline died disinherited. in 1436. Meanwhile, Gloucester married, his second wife being his former mistress, Eleanor Cobham, daughter of Reynold Cobham and Eleanor Colepeper. She was an enigmatic beauty with some of the dubious qualities of Lady Macbeth. In 1441, Eleanor was tried and convicted of practising witchcraft against the king in an attempt to retain power for her husband. She died in prison in Peel Castle, Isle of Man in 1454.

The children of Humphrey and Eleanor Cobham, born before marriage, were:

Arthur Plantagenet who died in 1447

Antigone Plantagenet born before 1428. She married Henry Grey, 2nd Earl of Tankerville, Lord of Powys. Henry died in 1449 and Antigone married  in 1451 John d'Amancier, Esquire of the Horse to Charles VII of France

Following his wife's conviction, Gloucester himself was arrested on a charge of treason.

In 1447 he was summoned by the King to attend a parliament at Bury St Edmunds, where he suddenly died on 23rd February 1447.  His corpse was taken to St Albans to be laid in a vault installed by his friend Abbot John of Wheathampstead. There was much talk that his convenient death had been contrived, but no legal accusation was made.

After inheriting the manor of Greenwich, Duke Humphrey enclosed Greenwich Park and from 1428 had a palace built there on the banks of the Thames, known as Bella Court and later as the Palace of Placentia. The Duke Humphrey Tower surmounting Greenwich Park was demolished in the 1660s and the site was chosen for building the Royal Observatory. His name lives on in "Duke Humfrey's Library", part of the Bodleian Library in Oxford, to which the Duke donated the nucleus of its collection. He was also a patron of literature, notably of the poet John Lydgate.