Organic pollution of rivers by wastewater discharge from human activities negatively impacts people and ecosystems. Without treatment, pollution control relies on a combination of natural degradation and dilution by natural runoff to reduce downstream effects. We quantify here for the first time the global sanitation crisis through its impact on organic river pollution from the threats of (1) increasing wastewater discharge due to urbanization and intensification of livestock farming, and (2) reductions in river dilution capacity due to climate change and water extractions. Using in-stream Biochemical Oxygen Demand (BOD) as an overall indicator of organic river pollution, we calculate historical (2000) and future (2050) BOD concentrations in global river networks. Despite significant self-cleaning capacities of rivers, the number of people affected by organic pollution (BOD >5 mg/l) is projected to increase from 1.1 billion in 2000 to 2.5 billion in 2050. With developing countries disproportionately affected, our results point to a growing need for affordable wastewater solutions.