The presence of antibiotics in surface waters poses risks to aquatic ecosystems and human health due to their toxicity and influence on antimicrobial resistance. After human consumption and partial metabolism, antibiotic residues are excreted and undergo complex accumulation and decay processes along their pathway from wastewater to natural river systems. Here, we use a global contaminant fate model to estimate that of the annual human consumption of the 40 most used antibiotics (29,200 tonnes), 8,500 tonnes (29%) are released into the river system and 3,300 tonnes (11%) reach the world’s oceans or inland sinks. Even when only domestic sources are considered (i.e. not including veterinary or industrial sources), we estimate that 6 million km of rivers worldwide are subject to total antibiotic concentrations in excess of thresholds that are protective of ecosystems and resistance promotion during low streamflow conditions, with the dominant contributors being amoxicillin, ceftriaxone, and cefixime. Therefore, it is of concern that human consumption alone represents a significant risk for rivers across all continents, with the largest extents found in Southeast Asia. Global antibiotic consumption has grown rapidly over the last 15 years and continues to increase, particularly in low- and middle-income countries, requiring new strategies to safeguard water quality and protect human and ecosystem health.