Primary-school children in low- and middle-income countries are often deprived of microbiologically safe water and sanitation, often resulting in a high prevalence of gastrointestinal diseases and poor school performance. We used Quantitative Microbial Risk Assessment (QMRA) to predict the probability of infection in schoolchildren due to consumption of unsafe school water. A multistage random-sampling technique was used to randomly select 425 primary schools from ten districts of Sindh, Pakistan, to produce a representative sample of the province. We characterized water supplies in selected schools. Microbiological testing of water resulted in inputs for the QMRA model, to estimate the risks of infections to schoolchildren. Groundwater (62%) and surface water (38%) were identified as two major sources of drinking water in the selected schools, presenting varying degrees of health risks. Around half of the drinking-water samples were contaminated with Escherichia coli (49%), Shigella spp. (63%), Salmonella spp. (53%), and Vibrio cholerae (49%). Southern Sindh was found to have the highest risk of infection and illness from Campylobacter and Rotavirus. Central and Northern Sindh had a comparatively lower risk of waterborne diseases. Schoolchildren of Karachi were estimated to have the highest probability of illness per year, due to Campylobacter (70%) and Rotavirus (22.6%). Pearson correlation was run to assess the relationship between selected pathogens. V. cholerae was correlated with Salmonella spp., Campylobacter, Rotavirus, and Salmonella spp. Overall, the risk of illness due to the bacterial infection (E. coli, Salmonella spp., V. cholerae, Shigella, and Campylobacter) was high. There is a dire need for management plans in the schools of Sindh, to halt the progression of waterborne diseases in school-going children.