Due to rapid development and population growth in Ghana’s urban and peri-urban areas, most freshwater resources are degrading, directly affecting residents in these vicinities. This study, therefore, evaluates how human activities such as urbanization, farming and industrialization affect the Bonsa River and the health-related quality of life of residents living downstream. The study adopted statistical package for the social sciences (SPSS) and partial least square structural equation modeling (PLS-SEM) to assess the data retrieved from the residents living in and around the Bonsa River in Tarkwa Nsuaem, Ghana. The study’s outcome reveals a positive and significant impact of land use change on freshwater resource degradation and poor health-related quality of life of the inhabitants in the catchment area. The study has numerous practical and policy implications for the government, environmental and healthcare industry, and policymakers.