William was born to an undistinguished family, in Wickham, Hampshire, and educated at a school in Winchester. He was appointed Justice in Eyre south of the Trent along with Peter Atte Wode in 1361, a position he held until about 1367. He became secretary to the constable of Winchester Castle and in that capacity learned a lot about building. This led to architectural work for King Edward III, for whom he reconstructed Windsor Castle whilst residing at Bear's Rails in Old Windsor. William was paid for these services by being given the incomes of various churches, and eventually, in 1362, he was ordained. He had shown considerable talent as an administrator and in June 1363 was appointed Lord Privy Seal and then in October 1366 he was elected Bishop of Winchester, and in 1367, Chancellor of England. He resigned this position in 1371 and began a long conflict with John of Gaunt. However, with the ascension of Richard II to the throne, William was reappointed Chancellor in 1389, retaining that office through 1391.
He had many ups and downs in his long career, but at the time of his death on 27 September 1404, he was one of the richest men in England. Much of his wealth went into the schools he patronized, but he also contrived to leave a fortune to a nephew, whose descendants include the Twisleton-Wykeham-Fiennes family.
His motto was 'Manners makyth man'. This, along with a coat of arms, were granted to him by the College of Arms and not acquired by descent. His biography was written by Bishop Lowth. He was also written about by Lord Brougham in his 'Old England's Worthies' (1857) and by Froissart. 'Manners Makyth Man' is also the motto of the establishments Wykeham founded, Winchester College and New College, Oxford, as well as the Australian school Sydney Technical High School.