Surface water quality in tropical, agriculture-dominated catchments faces intense pressure from human activities, yet comprehensive, index-based assessments for these regions remain limited. This study aimed to use an index-based assessment to examine the spatial and temporal changes in water quality within the Maziba catchment in southwestern Uganda, characterised by increasing land-use pressures. Monthly surface water samples were collected from 16 stations between July 2023 and June 2024 to analyse physicochemical parameters. The study employed the Weighted Arithmetic Water Quality Index (WAWQI) for assessing drinking water suitability, the Comprehensive Pollution Index (CPI) for evaluating aquatic ecosystem health, and a new combined risk framework to deliver an integrated, stakeholder-oriented assessment. WAWQI results ranged from “good” to “unfit for consumption”, with 69% of stations classified as “poor” to “unfit”. CPI indicated “slight pollution” on average. Notably, the integrated risk assessment did not classify any stations as “Low Risk”, while most were classified as “High Risk” (50.0%) or “Severe Risk” (18.8%). Human activities and seasonal changes have a significant impact on water quality deterioration in the Maziba catchment. The simultaneous decline in water suitability for drinking and ecosystem health underscores the need for integrated management strategies that target both diffuse and point-source pollution to protect public health and aquatic ecosystems.