Cunningham was born in Wimbledon, England, in July 13, 1791. He was sent to Brazil in 1814 on a two year expedition to collect plants for the British Royal Gardens. In 1816, he sailed to New South Wales, Australia, to continue the work of the botanist Robert Brown (who had been on the Matthew Flinders expedition). Working with John Oxley, he explored (and collected plants from) much of eastern Australia. He traveled the course of the Lachlan River, Macquarie River, Cudgegong River, Hunter River, Gwydir River, Dumaresq River, MacIntyre River, and Brisbane River, Pandora's Pass (1823), the Australian coastline between North West Cape and the Gulf of Carpentaria (and many other areas). In 1827, Cunningham discovered Darling Downs (named for Governor Ralph Darling, who supported the trip) in eastern Australia.

Although he returned to Britain briefly, Cunningham spent the rest of his life in Australia. He is buried in Sydney's Botanical Gardens.