He succeeded to the title 14 October 1617 on the death in infancy of his elder brother Henry Willoughby, 4th Lord Willoughby of Parham. Francis Willoughby was second son of William Willoughby, 3rd Lord Willoughby of Parham The young and unexpected death of his elder brother Henry made Francis successor to the hereditary peerage and seat in the House of Lords, the upper house of Parliament. Francis Willoughby was an early supporter of the Parliamentarian cause during the English Civil War but later became a Royalist. He twice served as governor of English colonies in the Caribbean. Francis Willoughby died without male heirs of his body and the title passed to his younger brother William Willoughby, 6th Lord Willoughby of Parham, the third son of William Willoughby, 3rd Lord Willoughby of Parham.