Water resources are among the fundamental resources that are the most threatened worldwide by various pressures. This study applied the Driver–Pressure–State–Impact–Response (DPSIR) framework as an innovative tool to better understand the dynamic interlinkages between the different sources of multiple stressors on aquatic ecosystems in Burkina Faso. The triangulation of evidences from interviews, literature reviews, and strategic simulations shows that several human impacts as well as climate change and its effects (such as the decrease of the water level, and the increase of the surface water temperature) are detrimental to fish productivity, abundance, and average size. Furthermore, the ongoing demographic and nutritional transition is driving cumulative pressures on water and fish resources. In this context, the development of aquaculture could offer alternative livelihoods and help fish stocks in natural ecosystems to recover, thereby reducing fishermen’s vulnerability and easing overfishing pressures. Further, the empowerment of the actors and their participation to reinforce fisheries regulation are required to escape the current “regeneration trap” and to achieve a sustainable management of aquatic ecosystems in Burkina Faso.