Water pollution is a major issue in Ghana with direct impacts on human health. However, the underlying drivers of exposure and risks are not comprehensively explored and understood, while the diseases continue posing huge burdens. The key question addressed is: what are the key drivers influencing the water–health nexus, particularly water-borne disease risks in the Odaw River basin, Ghana? Multiple approaches were integrated: qualitative system dynamic modeling and urban land-use change assessment. Multi-level stakeholder participation, including household surveys, focus group discussions, and workshops were employed in developing and identifying indicators and feedback loops. The results revealed that communities have access to water and sanitation, but water-borne diseases are still prevalent. Flooding influenced by poor land use planning and solid waste disposal are key risk factors, contributing to water pollution and disease outbreaks. The major land-use change is the conversion of natural to built-up areas, resulting in decreased urban vegetation cover and increased soil sealing, partly contributing to flood risk. Complex linkages and multiple feedback loops between land use, flooding, water pollution, and water-borne disease risks were identified. In addition to supplying safe drinking water and sanitation, multi-sectoral collaborations are required to co-design and implement integrated interventions, including flood risk reduction, urban land use plans, and improved waste management to reduce disease risks and promote health.