Francis was the eldest son of Sir Percival Willoughby and his wife Bridget. Francis was brought up initially at Middleton in Warwickshire, but from 1599 principally at Wollaton Hall. He was educated at Magdalen College, Oxford, from 1607, and entered Lincoln's Inn in 1609. He returned to live at Middleton with his family from 1615. He succeeded his father in 1643, but never lived at Wollaton Hall, which had been badly damaged by fire in 1642.
He married Lady Cassandra Ridgeway (d 1675), daughter of Thomas, Earl of Londonderry, in 1610, and had:
Correspondence and details relating to Sir Francis Willoughby are contained within Cassandra Willoughby's two-volume history of the Willoughby family, part of the Middleton Collection held at Manuscripts and Special Collections at the University of Nottingham (reference Mi LM 26-27), and published as :
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