The gut microbiota is considered a key ‘metabolic organ’. Its metabolic activities play essential roles complementary to the host metabolic functions. The interplays between gut microbes and commonly used non-antibiotic drugs have garnered substantial attention over the years. Drugs can reshape the gut microorganism communities and, vice versa, the diverse gut microbes can affect drug efficacy by altering the bioavailability and bioactivity of drugs. The metabolism of drugs by gut microbial action or by microbiota–host cometabolism can transform the drugs into various metabolites. Secondary metabolites produced from the gut microbial metabolism of drugs contribute to both the therapeutic benefits and the side effects. In view of the significant effect of the gut microbiota on drug efficiency and clinical outcomes, it is pivotal to explore the interactions between drugs and gut microbiota underlying medical treatments. In this review, we describe and summarize the complex bidirectional interplays between gut microbes and drugs. We also illustrate the gut-microbiota profile altered by non-antibiotic drugs, the impacts and consequences of microbial alteration, and the biochemical mechanism of microbes impacting drug effectiveness. Understanding how the gut microbes interact with drugs and influence the therapeutic efficacy will help in discovering diverse novel avenues of regulating the gut microbes to improve the therapeutic effects and clinical outcomes of a drug in precision.

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