Oral delivery of drugs continues to be the most preferred method of pharmaceutical administration, owing to its ease, non-invasiveness, and elevated patient compliance. Nonetheless, substantial interindividual variability in oral medication absorption and therapeutic efficacy presents significant clinical challenges that cannot be fully explained by conventional pharmacokinetic analyses alone. Recent research in pharmacomicrobiomics and nutritional pharmacology highlights how food and gut bacteria significantly affect how well drugs work in the body, including their availability and how they are processed. Dietary constituents affect gastrointestinal physiology by modifying pH, transit time, enzyme activity, and transporter expression, while the gut microbiota, consisting of trillions of metabolically active microorganisms, interacts directly with orally ingested medications through biotransformation, activation, degradation, or competitive inhibition. This thorough review analyses the complex relationship between diet, gut microbiome composition and function, and oral drug absorption, focusing on molecular mechanisms that influence drug dissolution, intestinal permeability, pre-systemic metabolism, and therapeutic efficacy, by looking at the latest understanding of how the microbiome affects drug metabolism, how diet and the microbiome interact with drugs, and what this means for Additionally, we investigate novel ways for microbiome regulation to enhance oral medication therapy and emphasise the prospective integration of pharmacogenomics and pharmacomicrobiomics within the framework of precision medicine. Understanding these multifactorial interactions is crucial for enhancing individualised drug therapy, reducing therapeutic variability, and progressing the framework of personalised pharmacotherapy in clinical practice.