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The rich biodiversity of southern Africa has to date been relatively unimpacted by the activities of modern society, but to what degree will this situation persist into the 21st century? We use a leading global environmental assessment model (IMAGE) to explore future land use and climate change in southern Africa under the scenarios developed by the Millennium Ecosystem Assessment. We assess the impacts on terrestrial biodiversity using the Biodiversity Intactness Index, which gives the average change in population size relative to the pre-modern state, across all terrestrial species of plants and vertebrates. Over the coming century, we project absolute declines in the average population sizes of these taxa that are two to three times greater than the reductions that have occurred since circa 1700. Our results highlight the immense challenges faced by efforts to reduce rates of biodiversity loss in southern Africa, even under relatively optimistic scenarios. These results stress the urgent need for better aligning biodiversity conservation and development priorities in the region. Furthermore, we suggest that context-sensitive conservation targets that account for the development imperatives in different parts of the region are needed.