Born in Parramatta, a settlement close to (and now a suburb of) Sydney, Hume began exploring as a teenager, and made several journeys before his famous 1824-25 expedition with William Hovell, which discovered the overland route between Sydney and Port Phillip Bay, on whose shores Melbourne now stands. This famous overland journey (Hume and Hovell expedition) is commemmorated by the Hume Highway, the principal road between Sydney and Melbourne. Hume and Hovell were also commemmorated by having their portraits printed on the Australian one-pound banknote between 1953 and 1966.
In 1828, he journeyed with Sturt into western New South Wales, where they discovered the Darling River, the Murray River's longest tributary.
Hume became a magistrate in Yass until his death.