The hydro- and morphodynamic processes within the Vietnamese Mekong Delta are heavily impacted by human activity, which in turn affects the livelihood of millions of people. The main drivers that could impact future developments within the delta are local stressors like hydropower development and sand mining, but also global challenges like climate change and relative sea level rise. Within this study, a hydro-morphodynamic model was developed, which focused on a stretch of the Tien River and was nested into a well-calibrated model of the delta’s hydrodynamics. Multiple scenarios were developed in order to assess the projected impacts of the different drivers on the river’s morphodynamics. Simulations were carried out for a baseline scenario (2000–2010) and for a set of plausible scenarios for a future period (2050–2060). The results for the baseline scenario indicate that the Tien River is already subject to substantial erosion under present-day conditions. For the future period, hydropower development has the highest impact on the local erosion and deposition budget, thus amplifying erosional processes, followed by an increase in sand mining activity and climate change-related variations in discharge. The results also indicate that relative sea level rise only has a minimal impact on the local morphodynamics of this river stretch, while erosional tendencies are slowed by a complete prohibition of sand mining activity. In the future, an unfavourable combination of drivers could increase the local imbalance between erosion and deposition by up to 89%, while the bed level could be incised by an additional 146%.