Sir William Skeffington (c. 1465 – 31 December 1535), was a Lord Deputy of Ireland.
William Skeffington was born in Skeffington Hall, Leicestershire, the eldest son of Thomas Skeffington by his wife, Mary. His brother John was the patriarch of the Massareene family. William was appointed High Sheriff of Leicestershire and Warwickshire for 1508, 1515 and 1521 in the reign of Henry VII and was knighted by that king for his services. In 1523, he received from Henry VIII property near Tunbridge that had belonged to the executed traitor Henry Stafford, 2nd Duke of Buckingham.
He was Master of the Ordnance and a knight of the shire (MP) for Leicestershire from 1529–1535 in the reign of Henry VIII. He was also in 1529 appointed Lord Deputy of Ireland to Henry's son, the duke of Richmond, the nominal Lord Lieutenant of Ireland. He crossed over in August 1529, but his power was so circumscribed by instructions from Henry that the head of the Fitzgeralds, Gerald, 9th earl of Kildare, and not Skeffington, was the real governor of Ireland. In May 1531 Skeffington accepted the formal submission of the Gaelic leader Hugh Duff O'Donnell in Drogheda.