Like his father, the 3rd Duke was active in politics, and served for seven years as Lord Lieutenant of Ireland. He was also a Member of Parliament from 1721 until his father's death sent him to the House of Lords in 1729.
In 1739, he was enlisted as a founding governor for the new children's charity, the Foundling Hospital, in Bloomsbury, London, which aimed to alleviate the problem of babies being abandoned by destitute mothers and ended up becoming a centre for British art and music. William Cavendish sold the Old Devonshire House at 48 Boswell Street, Theobald's Road in Bloomsbury. In 1734 Cavendish engaged architect William Kent to build a new Cavendish House in fashionable Picadilly.