William Wills trained as a doctor under his father's supervision. In addition to practicing medicine, Wills developed an interest in Australia and, in 1852, bought a share in a Melbourne gold mining company. Wills' sons migrated to Australia in early 1853 and Wills joined them in October of that year. He developed a medical practice on the Ballarat gold fields.
In 1860, Wills joined an ill-fated expedition with Robert O'Hara Burke (commonly known as 'The Burke and Wills Expedition') and traversed the continent from south to north, reaching the Gulf of Carpentaria. On the return journey the expedition suffered loss of life and members of the party separated. Ultimately, both Burke and Wills died en route back to Melbourne and only one member of the expedition survived.