© 2021 The Author(s)The recent mass mortality event of more than 330 African elephants in Botswana has been attributed to biotoxins produced by cyanobacteria; however, scientific evidence for this is lacking. Here, by synthesizing multiple sources of data, we show that, during the past decades, the widespread hypertrophic waters in Southern Africa have entailed an extremely high risk and frequent exposure of cyanotoxins to the wildlife within this area, which functions as a hotspot of mammal species richness. The hot and dry climatic extremes have most likely acted as the primary trigger of the recent and perhaps also of prehistoric mass mortality events. As such climate extremes are projected to become more frequent in Southern Africa in the near future, there is a risk that similar tragedies may take place, rendering African megafauna species, especially those that are already endangered, in risk of extinction. Moreover, cyanotoxin poisoning amplified by climate change may have unexpected cascading effects on human societies. Seen within this perspective, the tragic mass death of the world's largest terrestrial mammal species serves as an alarming early warning signal of future environmental catastrophes in Southern Africa. We suggest that systematic, quantitative cyanotoxin risk assessments are made and precautionary actions to mitigate the risks are taken without hesitation to ensure the health and sustainability of the megafauna and human societies within the region. © 2021 The Author(s)• Cyanotoxin is the most likely cause for the massive death of elephants in Botswana. • Mammal species hotspot in Africa is under increasing risk of cyanotoxin poisoning. • This tragic event serves as an alarming early warning signal of future catastrophes. • Systematic assessments on cyanotoxin risk are strongly suggested in Southern Africa.