The Bay of Bengal has been suffering from increasing frequency of large-scale die-off events for the past decades. Most frequently, these events are attributed to high-speed human development and its harmful effects on environment, which is nevertheless, the biggest challenges currently faced by the world. Increasing urbanization, environmental pollution and climate change are leading to unsustainable ecosystem exploitation and raising health and disease management challenges. Considerable modulations in major ecosystems and major disturbances in the global food chain are some of the most significant consequences of this uncontrolled urbanization. Global warming and El Niño events are few particular phenomena that drive mass deterioration of terrestrial foliages and fauna as well as aquatic organisms, respectively. We here review and discuss the die-off events occurring in the Bay of Bengal for the last decades as well as all the data obtained from the analyses of such events to provide a future perspective on potential management and monitoring strategies directed towards the protection of the flora and fauna of several major ecosystems from such die-off events.