Pharmacomicrobiomics investigates the complicated relationship between the gut microbiome and medications, highlighting how the microbiome affects drug absorption, metabolism, and overall treatment outcomes. The interaction between pharmaceutical agents and the host microbiota is inherently bidirectional and complex. While the administration of various drugs can alter the composition and diversity of the gut microbial community, the intestinal microbiota, in turn, plays a crucial role in modulating fundamental pharmacokinetic and pharmacodynamic processes, which in turn affect the efficacy and safety of drugs. Microbial communities can influence the metabolism and efficacy of many medications in two primary ways: directly and indirectly. Direct mechanisms typically entail the induction of biochemical alterations and multiple transformations directly on the drug, whereas indirect mechanisms encompass modifications in host metabolism, alterations in the gut microbial community, the synthesis of various metabolites, and interactions with the host immune system, which indirectly influence the drug's metabolism, absorption, and efficacy. For instance, microbial communities play an important part in activating prodrugs like sulfasalazine, improving the outcomes of immunotherapy, and minimizing toxicity through specific interventions. Nonetheless, barriers can also emerge from the microbial breakdown of medications, reducing their therapeutic efficacy, along with adverse reactions mediated by microbiota. Innovations like probiotics, fecal microbiota transplantation, and microbiota profiling have shown promise in enhancing these interactions. Utilizing the distinct microbiota composition of individuals, pharmacomicrobiomics offers a route to personalized, precise, and safer therapies, signaling an important evolution in drug development and clinical practice. This study aims to provide a comprehensive overview of microbiome-drug interactions, with a particular focus on the influence of gut microbiota on drug efficacy, and to highlight their potential to revolutionize precision medicine.