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In sub-Saharan Africa, land cover change, expansion of hydropower infrastructure, and increased flooding complicate country-level efforts to meet the Sustainable Development Goal target concerning access to safe water. The Water, Energy and Food (WEF) nexus approach recognises that addressing these complex challenges requires cross-sectoral analyses at multiple scales. Building on such an approach, our study examined the interrelationships between land cover change, dam-related flooding and access to safe water via a national-level spatial analysis with local case studies in Malawi and Ghana. Our assessment of the water–food interactions found that areas of overlap between water points and cropland increased from 2000 to 2020 for both countries at national scale, but overlap extent varied greatly depending on the land cover product used. Local-scale exploration of water point installation patterns in Zomba, Malawi confirmed this pattern, highlighting increasing non-governmental funding of borehole installation programmes. Our assessment of water–energy interactions found that flooding mediated by hydropower dams increased for the White Volta Basin in Ghana, thereby increasing inundation of groundwater points. Local-scale focus group discussions revealed flooding resulted in contaminated water sources and high risk of injury or drowning whilst fetching water. Overall, our study highlights how socio-economic drivers are bringing water points, flooding and cropland into closer proximity, requiring flood mitigation measures at water points and agro-chemical management to minimise potential water quality impacts. Given differences between land cover products, we recommend more robust integration of existing land cover products to better monitor these phenomena.