The Mulligan River springs occur on the eastern edge of the Simpson Desert in far south-west Queensland, near the north-west margin of the Great Artesian Basin, and are associated with the Toomba Thrust Fault. The springs provide the only permanent surface water in the driest part of Australia. They have been focal points for human and animal activity for millennia, but despite their cultural and ecological interest, they have received relatively little attention compared to other Great Artesian Basin spring groups. Here we explore the hydrogeology, cultural history and ecology of these springs through a review of published literature, early explorer journals, diaries and letters of early settlers, books, and comprehensive field survey. Fragments of stories and dense surface archaeology indicate intensive occupation at many of the springs by the Wangkamadla people for thousands of years, but most of the knowledge about how people used, mythologised and managed the springs did not survive the frontier period that saw the area depopulated. From the 1880s, explorers and pastoralists marvelled at, relied upon and in many cases severely modified the springs. Shallow bores were sunk on or near springs, and others were excavated to improve cattle access. Today, all except three of 90 documented springs remain active, although many are highly modified and reductions in flow and wetland extent due to aquifer drawdown are likely to have occurred. No endemic species are known to be associated with the Mulligan River springs, but they support disjunct populations of some plants and fish. There appears to be considerable natural dynamism in spring activity and flow, but springs in some areas have emerged or become reactivated, apparently due to increased aquifer pressure following bore capping. Additional springs were found during the most recent surveys, and a small number probably remain undocumented. Improved understanding of recharge areas, aquifer connectivity and spring dynamism will inform future management of these isolated oases, while detailed archaeological work will shed light on patterns of Aboriginal use and better situate the springs in the wider cultural landscape.