Anthropogenic activities threaten surface water quality across the globe, especially in contexts where monitoring is non-existent or weak. Our understanding of the effect, order and magnitude of natural and human-induced environmental factors on surface water quality is limited. This study assessed the effect, predictive order and magnitude of natural and human-induced environmental variables on surface water quality in the Birim North District of Ghana. Approximately 540 samples were collected from 15 rivers and streams in 2018 and analysed using 31 indicators. Landsat satellite images (2018 and 2019) of the study area were analysed for land use land cover data. The data were fitted to ordinary least squares (OLS) regression model. Season (50%) most accounted for variability in the surface water quality whereas elevation and forest cover accounted for 28% and 21%, respectively. Surface water quality in the Akoase and Nyafoman/Noyem clusters were 30% and 10% respectively better in quality than the Adofokrom/Amenam cluster. The increasing order of magnitude of variables in predicting surface water quality was Buffer, Cultivated area, Built-up, Forest, Rivers and streams cluster, Elevation, and Season. Consequently, management interventions for surface water ecosystems should account for spatio-temporal heterogeneity in the factors that influence surface water quality.