He became one of Thomas Cromwell's "visitors of the monasteries" when King Henry VIII annexed the property of the Catholic Church at the end of the 1530s, in the dissolution of the monasteries. This followed from his successful career as a financial expert holding public office in the Exchequer, which led to his wealth. He was accused of accumulating extra riches unfairly during the dissolution.
During the reign of Mary I of England, a favourable biography of Thomas Cardinal Wolsey was first published, written from the perspective of one of his closest aides, the one who had taken King Henry news of Wolsey's death. Although for centuries Sir William was said to be its author, historians now attribute it to his older brother George Cavendish (1494 - ~1562) instead.
His first two wives died, leaving him with two daughters.
In 1547 he married Bess of Hardwick. He sold his property in Suffolk and moved to Bess's native county of Derbyshire. He purchased the Chatsworth estate in 1549 and the couple began to build Chatsworth House in 1553.
In the ten years before he died, they had eight children, only six of whom survived infancy; one of these, Elizabeth, later entered into a controversial marriage with the Earl of Lennox. Their daughter Frances Cavendish, married Henry Pierrepont. Some of William and Bess's descendants became the Dukes of Devonshire, and others became Dukes of Newcastle. Their granddaughter Arbella Stuart was a claimant to the throne of England in 1603.