He was born the eldest son of Henry Spelman (d. - 1581), of Congham, and the grandson of Sir John Spelman (1495-1544). Educated at Trinity College, Cambridge in 1583, he later married Eleanor l'Estrange in 1590.
Spelman entered parliament as member for Castle Rising in 1593 and 1597-98. Knighted in 1603, he was appointed High Sheriff of Norfolk in 1604. In 1612, he settled in London near his friend Sir Robert Bruce Cotton. In 1617, he served on a commission to inquire into disputed Irish estates, and later took part into legal inquiries into the exactions levied on behalf of the Crown in the civil and ecclesiastical courts. Henry Spelman continued to rise in prestige served as a member of the Parliament of England for Worcester in 1625.. In 1627, he became treasurer of the Guiana Company, and he was also an energetic member of the council for New England. His general services to the state were recognized in 1636 by a gift of money and two years later by the offer of the mastership of Sutton's Hospital, Charterhouse.
He died in London in October 1641, and was buried in Westminster Abbey. His later years had been spent in the house of his son-in-law, Sir Ralph Whitfield, and he was survived by son John Spelman.