Despite growing evidence of the deleterious effects on ecological and human health, little is known regarding the global occurrence of pharmaceuticals in rivers. Studies assessing their occurrence are available for 75 of 196 countries, with most research conducted in North America and Western Europe. This leaves large geographical regions relatively unstudied. Here, we present the findings of a global reconnaissance of pharmaceutical pollution in rivers. The study monitored 1,052 sampling sites along 258 rivers in 104 countries of all continents, thus representing the pharmaceutical fingerprint of 471.4 million people. We show that the presence of these contaminants in surface water poses a threat to environmental and/or human health in more than a quarter of the studied locations globally.Environmental exposure to active pharmaceutical ingredients (APIs) can have negative effects on the health of ecosystems and humans. While numerous studies have monitored APIs in rivers, these employ different analytical methods, measure different APIs, and have ignored many of the countries of the world. This makes it difficult to quantify the scale of the problem from a global perspective. Furthermore, comparison of the existing data, generated for different studies/regions/continents, is challenging due to the vast differences between the analytical methodologies employed. Here, we present a global-scale study of API pollution in 258 of the world’s rivers, representing the environmental influence of 471.4 million people across 137 geographic regions. Samples were obtained from 1,052 locations in 104 countries (representing all continents and 36 countries not previously studied for API contamination) and analyzed for 61 APIs. Highest cumulative API concentrations were observed in sub-Saharan Africa, south Asia, and South America. The most contaminated sites were in low- to middle-income countries and were associated with areas with poor wastewater and waste management infrastructure and pharmaceutical manufacturing. The most frequently detected APIs were carbamazepine, metformin, and caffeine (a compound also arising from lifestyle use), which were detected at over half of the sites monitored. Concentrations of at least one API at 25.7% of the sampling sites were greater than concentrations considered safe for aquatic organisms, or which are of concern in terms of selection for antimicrobial resistance. Therefore, pharmaceutical pollution poses a global threat to environmental and human health, as well as to delivery of the United Nations Sustainable Development Goals.