Seymour was the grandson of Edward Seymour, 1st Earl of Hertford and Catherine Grey, which thus gave him a distant claim to the throne through the latter's descent from Mary Tudor, younger sister of Henry VIII. His parents were Edward Seymour, Lord Beauchamp of Hache, and Honora Rogers. William was the great-grandson of the first Duke of Somerset.
He married, firstly, Arbella Stuart, daughter of Charles Stuart, 1st Earl of Lennox and Elizabeth Cavendish, on 22 June 1610, in a secret marriage. Arbella was thirteen years his senior, and the marriage was disapproved of by King James I of England - the marriage of two potential pretenders to the throne, who were fourth and sixth in line to the English throne, could only be seen as a threat to the ruling dynasty. As a result, William was condemned to life imprisonment in the Tower of London (thus becoming the fourth of five generations of Seymours to spend time in the Tower). In June of 1611, he escaped from the Tower, and planned to meet up with Arbella and flee to the Continent; bad weather and other circumstances prevented their meeting, and Arbella was recaptured and herself placed in the Tower, while William managed to reach safety abroad. Arbella died in 1615, without their ever being reunited.
Seymour married, secondly, Lady Frances Devereux, daughter of Robert Devereux, 2nd Earl of Essex and Frances Walsingham, daughter of Francis Walsingham, on 3 March 1616 at Drayton Bassett, and had seven children:
Seymour, who succeeded his grandfather as Earl of Hertford in 1621, became a prominent member of the opposition to King Charles I in the House of Lords, supporting the Petition of Right of 1628, and co-signing the letter of the 12 Peers of 1640, along with his brother-in-law the Earl of Essex.
However, Hertford parted company with the more radical opponents of the King in the Long Parliament in 1641, and was created Marquess of Hertford by the King. In the Civil War, Hertford, along with such figures as Sir Edward Hyde, was a moderate royalist, and throughout sought a compromise settlement, continuing unofficial negotiations with his brother-in-law Essex, who became the Parliamentary commander, throughout the war. He was nevertheless a trusted supporter of the King, who made him guardian of his son the Prince of Wales, and who undertook several important military commands in royalist service over the course of the war, commanding troops from South Wales.
After the end of the First Civil War and the King's imprisonment, Hertford was the most prominent nobleman to remain alongside the king throughout his captivity, and was with him up until his execution in 1649. During the Interregnum, Hertford largely kept himself away from both politics and royalist conspiracies, believing that the monarchy would be restored given time, and that conspiracies would only delay the restoration.
When the Restoration came in 1660, Hertford was restored to all his former positions, and his services in the Royalist cause were further recognised by Charles II who restored Hertford to his great-grandfather's dukedom of Somerset which had been forfeited in 1552. He died at Essex House, London and was buried on 1 November 1660 at Great Bedwyn, Wiltshire. He was succeeded by his grandson William Seymour.