Eldest son and heir of Sir John Willoughby and Anne Cheney. Created 1st Lord Willoughby of Broke in 1491, the title being derived from Broke in Wiltshire, which he inherited through his mother.

Lord Broke maneuvered successfully during the War of the Roses; in 1470, fighting for the Yorkists, he battled against the Lancastrian Richard Edgecombe of Cotehele. He served as a Justice of the Peace for Devonshire in 1482-3. Late in 1483, Broke changed sides and joined in Buckingham's unsuccessful rebellion against Richard III. He was attainted and lost his lands to a cousin, but regained them after fighting for Henry Tudor at Bosworth.

He was made a Knight of the Garter in 1488 and held numerous offices under Henry VII. He was receiver of the Duchy of Cornwall in 1485, Lieut. of Braden Forest in Lancaster in 1486, King's Councillor and Lord Steward of the Household; in the latter capacity he arranged the journey of Catherine of Aragon from Plymouth to London in 1501.

Willoughby was appointed Captain-general of the force sent to Brittany in 1489, was Marshal of the army against France in 1492 and served as Commissioner in the expedition against Scotland (during the Perkin Warbeck rebellion) in 1487.

Early in the reign of Henry Tudor, Willoughby laid claim to the Barony of Latimer, which title he had right to through his great grandmother Elizabeth Nevill. The title was at this time held by Richard Nevill and eventually the two reconciled with an agreement to exchange certain lands and a promise of marriage between Willoughby's grandson and Nevill's eldest daughter; Richard retaining the Latimer title.

Willoughby married Blanch, daughter and co-heir of John Champernoun, of Beer Ferrers and Callington, with whom he had three children: Robert, his son and heir, Elizabeth, wife of John, Lord Dynham and Anthony Willoughby, Kt. He also left a bastard son, Nicholas, whose mother was Agnes Whitehead.