In late 2018 to early 2019, three significant fish death events occurred in the Lower Darling River, Australia, with mortality estimates of millions of fish. We examined the proximate and ultimate causes of these events. We determined that not only were the conditions existing at the time a significant contributing factor, but that antecedent conditions, particularly during the period 2010–17, also contributed. The extreme hot and dry climate during 2018, extending into 2019, shaped the conditions that saw a large fish biomass, which had flourished in the Darling River and Menindee Lakes since favourable spawning conditions in 2016, isolated in weir pools, with no means of escaping upstream or downstream. Strong and persistent weir pool stratification created hypoxic conditions in the hypolimnion. A series of sudden cool changes subsequently initiated rapid and sudden mixing of the stratified waters, causing depletion of oxygen throughout the water column and resulting in the fish deaths. The events were also shaped by broader climatic, hydrological and basin management contexts that placed the Lower Darling River at risk of such fish deaths. Our observations have implications for future river management, and we make several suggestions how policy makers and river operators can minimise fish death risks into the future.