The Mekong, one of the world’s most iconic waterways, faces a myriad of challenges, predominantly in its lower reaches. The compounding effects of climate change and upstream developmental projects exacerbate existing issues. The Lower Mekong region, including Cambodia, Laos, Thailand and Vietnam, is especially susceptible to the adverse impacts of changing climate and human activities along the river. Notably, the delta and the Tonlé Sap will bear the brunt of upstream governments prioritizing their national interests over regional well-being, risking a potential catastrophe. Rising temperatures and unpredictable rainfall patterns are causing water scarcity in the Lower Mekong region, compounded by El Niño-induced droughts over Southeast Asia, which may result in crop failures and food insecurity. Paradoxically, the Lower Mekong may also see more frequent floods due to intensified rainfall caused by erratic weather patterns and upstream dam operations, with resultant irregularities in water flows leading to riverbank erosion, flooding of farmland, displaced communities and property damage. Rising temperatures will likely result in saltwater intrusion into the river’s estuaries, rendering large areas of arable land unsuitable for rice cultivation. Managing the Mekong’s water resources involves a complex balance of cooperation and competition among neighbouring nations. Climate change can heighten vulnerabilities and worsen disputes over water distribution, underscoring the need for effective regional diplomacy. Cooperation at local, national and international levels is crucial because climate change and natural variations transcend borders, and the future of the Mekong hinges on a collective response to these urgent issues.