Antibiotics have received extensive attention due to their sophisticated effects on human health and ecosystems. However, there is an extreme scarcity of information on composition, content, geographic distribution, and risk of riverine antibiotics at a large spatial scale. Based on a systematic review of over 600 pieces of literature (1999–2021), we established a global dataset containing more than 90,000 records covering 169 antibiotics and their metabolites in surface water and sediment across 76 countries. The occurrence of prioritized antibiotics largely depended on socioeconomic developmental levels, and the current “hotspots” of polluted rivers were found mostly in less developed countries or emerging economies (e.g., some in Africa, South America, and Asia). By developing the screening protocol for risk-based prioritization of antibiotics, we advanced a rank list of antibiotics for guiding formulation of region-specific strategies, which highlighted the importance of whole life cycle management of antibiotics in health maintenance of the world’s rivers.