This is the first study using detailed retrospective medication usage data from electronic health records to systematically assess the long-term effects of medication usage on the gut microbiome. We identified carryover and additive effects on the gut microbiome for a range of antibiotics and non-antibiotic medications, such as benzodiazepine derivatives, antidepressants and glucocorticoids, among others. These findings highlight a collateral effect of diverse drug classes on the gut microbiome, which warrants accounting for long-term medication usage history when assessing disease-microbiome associations.