River water quality has been increasingly deteriorated because of the influence of natural process and anthropogenic activities. Quantifying the influence of landscape metrics, namely topography and land use pattern, which encompass land use composition and landscape configuration, across different spatial and seasonal scales that reflect natural process and anthropogenic activities, is highly beneficial for water quality protection. In this study, we focused on investigating the effects of topography, landscape configuration and land use composition on water quality at different spatial scales, including 1-km buffer and sub-watershed, and seasonal scales, including wet and dry season, based on the monthly water quality data in 2016 of Dongting Lake in China. Multivariate statistical analysis of redundancy analysis and partial redundancy analysis was used to quantify the contributions of these factors under different scales. Our results showed that among the three environmental groups, topography made the greatest pure contribution to water quality, accounting for 11.4 to 30.9% of the variation. This was followed by landscape configuration, which accounted for 9.4 to 23.0%, and land use composition, which accounted for 5.9 to 15.7%. More specifically, water body made the greatest contribution to the water quality variation during dry season at both spatial scales, contributing 16.6 to 17.2% of the variation. In contrast, edge density was the primary interpreter of the variability in water quality during wet season at both spatial scales, accounting for 9.9 to 11.1% of the variation. The spatial variability in the influence of landscape metrics on water quality was not markedly distinct. However, these metrics have a minimal impact difference on water quality at the buffer scale and the sub-watershed scale. Moreover, the contribution of landscape configuration varied the most from the buffer to sub-watershed scales, indicating its importance for the spatial scale difference in water quality. The findings of this study offer useful insights into enhancing water quality through improved handling of landscape metrics.