The relationship between the ever-increasing cancer mortality and water pollution is an important public concern in China. This study aimed to explore the association between serious water pollution and increasing digestive cancer mortality in the Huai River Basin (HRB) in China. A series of frequency of serious pollution (FSP) indices including water quality grade (FSPWQG), biochemical oxygen demand (FSPBOD), chemical oxygen demand (FSPCOD), and ammonia nitrogen (FSPAN) were used to characterize the surface water quality between 1997 and 2006. Data on the county-level changing mortality (CM) due to digestive tract cancers between 1975 and 2006 were collected for 14 counties in the study area. Most of investigated counties (eight) with high FSPWQG (>50%) distributed in the northern region of the HRB and had larger CMs of digestive tract cancers. In addition to their similar spatial distribution, significant correlations between FSP indices and CMs were observed by controlling for drinking water safety (DWS), gross domestic product (GDP), and population (POP). Furthermore, the above-mentioned partial correlations were clearly increased when only controlling for GDP and POP. Our study indicated that county-level variations of digestive cancer mortality are remarkably associated with water pollution, and suggested that continuous measures for improving surface water quality and DWS and hygienic interventions should be effectively implemented by local governments.