Henry Wriothesley succeeded to his father's earldom in 1581 and became a royal ward under the care of Lord Burghley, Educated at the University of Cambridge and at Gray's Inn, London, he was 17 when he was presented at court, where he was favoured by Queen Elizabeth I and befriended by Robert Devereux, 2nd Earl of Essex, Southampton became a munificent patron of writers, including Barnabe Barnes, Thomas Nashe, and Gervase Markham. Southampton is best known as the patron of Shakespeare, who dedicated Venus and Adonis (1593) and The Rape of Lucrece (1594) to him. It has also been argued, albeit inconclusively, that the sonnets were addressed to him. If so, the earlier sonnets, urging marriage, must have been written before the beginning (in 1595) of Southampton's intrigue with Elizabeth Vernon, one of the queen's waiting women, which culminated with their hasty marriage in 1598, incurring the queen's wrath and leading to their brief imprisonment.

In 1596 and 1597 Southampton accompanied Essex on his expeditions to Cadiz and to the Azores. In 1599 he went to Ireland with Essex, but the queen insisted that Southampton return to London. He was deeply involved in the Essex rebellion (February, 1601) on the eve of which he induced players at the Globe Theatre to revive Richard II, a play dealing with the deposition of a king, in order to sitr up the populace. He was tried for treason on Feb. 19, 1601; his titles were forfeited and he was condemned to death, but his sentence was commuted to life imprisonment through the intervention of Sir Robert Cecil.

On the accession of James I, Southampton he was released from prison and resumed his place at court. He was made a Knight of the Garter and captain of the Isle of Wight in 1603 and was restored to the peerage hy act of Parliament. In 1603 he entertained Queen Anne with a performance of Love's Labour's Lost by Richard Burbage and his company, to which Shakespeare belonged.

Southampton was an active member of the Virginia and East India companies. He was a volunteer in support of German Protestants in 1614 and in 1617 proposed fitting out an expedition against the Barbary pirates. He became a privy councillor i 1619 but fell into disgrace through his determined opposition to the royal favoroute, the duke of Buckingham. In 1624, he and his elder son volunteered to fight for the United Provinces against Spain, but on landing in the Netherlands they were attacked with fever, and Southampton died a few days later after the death of his son.