Analyses of pollen, diatoms, XRF geochemistry, and pigments provide a unique window into how an insular ecosystem in Mauritius responded to an extreme drought event 4200 years ago. We provide a reconstruction of regional vegetation change and local wetland development under influence of sea level rise and inferred climate change between 4400 and 4100 cal. yr BP. Our multi-proxy data evidence a severe drought between 4190 and 4130 cal. yr BP, which ultimately led to mass mortality of larger vertebrates, including two species of giant tortoises and dodos in a <2-ha region. This prolonged drought around the Indian Ocean is recorded in many regions dependent on monsoon precipitation and is suggested to cause the collapse of human societies in East Africa and India. We demonstrate a direct relation between the mass mortality events in the Mare aux Songes (MAS) rock valley and the 4200 cal. yr BP drought. MAS represents a fresh water source that attracted and concentrated vertebrates. Abrupt increased aridity induced regional fires on Mauritius and caused decreased water levels, and a shrinking water surface resulting in further concentration of the animals in this coastal site. Upconing of the saline wedge underlying the fresh water source induced progressive salinization. The excrements of the animals produced hypertrophic conditions that, combined with salinization and high temperatures, created a suitable environment for potentially toxic cyanobacteria. These factors led to a deadly cocktail, resulting in the death of 100,000s of vertebrates by intoxication, dehydration, trampling, and miring, and promoted a unique conservation of fossils. The ‘4.2 ka megadrought’ likely induced similar bottlenecks elsewhere in the SW Indian Ocean region.