The annual flood pulse of the Mekong River is crucial to sustain agriculture production, nutrition, and the livelihood of millions of people living in the Vietnamese part of the Mekong Delta (VMD). However, climate change impacts on precipitation, temperature and sea-level combined with land subsidence, upstream hydropower development, and water infrastructures (i.e. high-dykes construction) are altering the hydrological regime of the VMD. This study investigates future changes in flood hazard and agricultural production caused by these different scales of human-induced stresses. A quasi- two-dimensional (quasi-2D) hydrodynamic model was used to simulate eight scenarios representing the individual and compound impacts of these drivers for a baseline (1971-2000) and future (2036-2065) period. The scenarios map the most likely future pathway of climate change (RCP 4.5) combined with the best available Mekong upstream hydropower development, and land subsidence scenarios as well as the current delta development plan. We found that sea-level rise and land subsidence would cause the highest changes in flood hazard and damage to rice crop, followed by hydropower and climate change impacts. Expansion of high-dyke areas in two northernmost delta provinces (An Giang and Dong Thap) would have the smallest impact. The combination of all modelled drivers is projected to increase delta inundation extent by 20%, accompanied with prolonging submergence of 1-2 months, and 2-3 times increase in annual flood damage to rice crops in the flood-prone areas of the VMD. These findings of likely increasing risk of tidal induced flood hazard and damage call for well-planned adaptation and mitigation measures, both structural and non-structural.