Climate change impacts on large river basins, such as the Mekong River Basin (MRB), are complex due to shared governance and interconnected socioeconomic areas, making them highly vulnerable to change. The MRB, spanning six countries including Thailand, is crucial for the food and economic security of > 60 million people. However, in 2021, Thailand was ranked as the 9th highest risk country affected by climate change. To integrate climate adaptation in Thailand's MRB, we examined the effects of climate change on rapidly developing farmer and fisher communities in northeastern Thailand and explored feasible adaptation options. Using an interdisciplinary approach that included literature review, participatory action methods, and the resist-accept-direct (RAD) framework, we found that climate change is projected to increase temperatures, precipitation, extreme events, erosion, and water clarity, while decreasing heavy sediment transport. These changes negatively impact agriculture, fisheries, human health, and tourism. We identified several adaptation strategies across environmental, ecological, and human health categories to accommodate local needs, such as preventing habitat degradation (e.g., from dams and deforestation), providing fish refuge and passage, and supporting technical capacity. Community-driven adaptation planning and implementation are essential for supporting global sustainable development in a changing climate.