The spatial relationships between land uses and river-water quality measured with biological, water chemistry, and habitat indicators were analyzed in the Little Miami River watershed, OH, USA. Data obtained from various federal and state agencies were integrated with Geographic Information System spatial analysis functions. After statistically analyzing the spatial patterns of the water quality in receiving rivers and land uses and other point pollution sources in the watershed, the results showed that the water biotic quality did not degrade significantly below wastewater treatment plants. However, significantly lower water quality was found in areas downstream from high human impact areas where urban land was dominated or near point pollution sources. The study exhibits the importance of integrating water-quality management and land-use planning. Planners and policy-makers at different levels should bring stakeholders together, based on the understanding of land–water relationship in a watershed, to prevent pollution from happening and to plan for a sustainable future.