The Mekong River (MR) is recognized the 12th biggest rivers in the world. The Mekong watershed is the biggest one in Southeast Asia (795,000 km2), is densely populated (70 million people), is considered as the most productive one in Southeast Asia and is economically essential to the region. However, nowadays, the Lower Mekong River (LMR) and its delta are facing several emerging and critical anthropogenic stressors (dams construction, climate change, water poor quality, delta sinking). This review attempts to: (i) present the Mekong regional characteristics (geography, topological settings, climatic conditions, hydrology, demographic features and the anthropogenic activities), (ii) present the different factors that endanger the LMR, including the dam’s impacts, the climate change, the delta subsidence, and the degradation of the water quality, (iii) make comparison with different big rivers around the world and (iv) promote future decisions in order to minimize the negative impacts and seek for a trajectory that assures well-being and sustainability. International consultation and cooperation leading to sustainable management is now of a pivotal importance to try to avoid the deterioration of the LMR and its delta.