The deterioration of water quality has become a primary environmental concern worldwide. Understanding the status of water quality and identifying the influencing factors are important for water resources management. However, reported analyses have mostly been conducted in small and focused areas. It is still unclear if factors driving spatial variation in water quality would be different in extended spatial scales. In this paper, we analyzed spatial pattern of inland surface water quality in China using a dataset with four water quality parameters (i.e., pH, DO, NH4+-N and CODMn) and the water quality level. We tested the effects of anthropogenic (i.e., land use and socio-economic) and natural (i.e., climatic and topographic) factors on spatial variation in water quality. The study concluded that the overall inland surface water quality in China was at level III (fair). Water quality level was strongly correlated with CODMn and NH4+-N concentration. In contrast to reported studies that suggested land use patterns were the determinants of inland surface water quality, this study revealed that both anthropogenic and natural factors played important roles in explaining spatial variation of inland surface water quality in China. Among the tested explanatory variables, mean elevation within watershed appeared as the best predictor for pH, while annual precipitation and mean air temperature were the most important explanatory variables for CODMn and DO, respectively. NH4+-N concentration and water quality level were most strongly correlated with the percent of forest cover in watershed. Compared to studies at smaller spatial scales, this study found different influencing factors of surface water quality, suggesting that factors may play different roles at different spatial scales of consideration. Therefore management policies and measures in water quality control must be established and implemented accordingly. Since currently adopted parameters for monitoring of inland surface water quality in China are largely influenced by natural variables, additional physicochemical and biological indicators are needed for a robust assessment of human impacts on water quality.