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Rice is one of the most important agricultural commodities throughout the Mekong River Basin including the Tonle Sap Lake floodplains in Cambodia. Recent increases in hydropower dams along the Mekong River have likely altered the surface water hydrology impacting the arable areas and soil qualities for rice production in the Tonle Sap lowland. Along with the hydrological impacts, the region’s rice farming is facing a rapidly changing climate. It is critical to understand how the hydrological changes associated with dam development impact the region’s rice production in a changing climate. The aims of this study were to assess the impacts of recent increases in hydropower dams on the timing and areas of rice cropping in the Tonle Sap floodplains and to evaluate the effects of changing hydrology, rising temperature, and adaptive farming practices on rice productivity using a process-based rice crop model: ORYZA (v3). The effect of dams on arable areas for rice was identified by a remote-sensing method based on the PhenoRice algorithm for the period of 2001–2019 in two rice-growing provinces: Kampong Thom and Battambang. The PhenoRice method identified an increase in rice growing areas as well as shifts in both timing and location of rice cropping towards the sources of irrigation during the dry season since 2010. The ORYZA model simulated a substantial yield reduction with an increase of 2 °C in air temperature in the region. The model predicted that the rice productivity in the region is sensitive to soil organic carbon content which is expected to change with surface water hydrology. The model also predicted that region’s rice yield can increase by optimizing the timing and amount of N fertilization. The findings from this study highlight how hydrology, climate, and agronomic practices can interact to impact rice production in the Lower Mekong Region and provide insights for effective water management and agronomic practices to attain food security in the region in a changing climate.