The climate is changing rapidly due to global warming caused by population increase and urbanization. The Mekong River Basin is heavily affected by climate change and anthropogenic activities such as river damming, land use change, and dyke construction, leading to extreme floods and drought occurring more frequently and unpredictably. Consequently, wetland compartments are disconnected from the main rivers, causing a lack of fresh water and nutrients for paddy fields in the Mekong Delta. Therefore, agricultural yield and productivity in the Mekong Delta have decreased, causing difficulties for local people and food insecurity in the region. This research aims at 1) holistically assessing individual and compound effects of climate change and human activities on streamflow and sediment in the entire Mekong Basin, 2) addressing the compound effects of climate-induced and man-made floods and droughts on agricultural practices, 3) proposing a comprehensive guideline to exploit flood water and sediment for agricultural cultivation, 4) developing a nature-based solution (i.e., floating rice) to support regional and global food security and enhance the income of farmers in the Mekong Delta, and 5) developing the capacity of early-career professionals, policymakers, stakeholders, and the local community. The project results are highly transferable to other river basins in the Asia-Pacific region and worldwide regions under a regional collaborative network and international agendas.