Integrating local knowledge and scientific information can aid in co-developing locally relevant approaches for climate change adaptation and disaster risk reduction. Communities along the Mekong River have adapted to variability in temperature, rainfall, and flooding patterns over time. Rapid environmental change in the Mekong Basin presents a new set of challenges related to drought, altered seasonal rainfall, more frequent high-flow flood events, and water withdrawals for hydropower and irrigation. We present a multi-method approach to understand how local knowledge of the spatial and temporal patterns of floods, droughts, and rainfall can be integrated with scientific information along a flood-prone section of the lower Mekong River in Kratie Province, Cambodia. Participatory hazard mapping of community members’ knowledge of the movement of floodwaters through the landscape enabled interpretation of flood extent mapping using Synthetic Aperture Radar images from the Sentinel-1A satellite. Seasonal calendars of weather patterns and livelihood activities, together with local indicators of flooding, rainfall, and drought were compared with trends in 35 years of rainfall data, and highlighted “pressure points” at the beginning and end of the rainy season where agriculture may be particularly impacted by climate change. We discuss potential applications of our findings for adaptation and hazard planning.