The human biological system consists of trillions of microscopic living organisms that are connectively responsible for maintaining the homeostasis of the human body; those are called microbiomes. The changes in the microbiome environment of the system may lead to some pathological conditions like diabetes, cancer, allergy, obesity, and gastrointestinal tract (GIT) diseases. Microbiota is responsible for the absorption and metabolism of the drug. Recent clinical trials on microbiomes show some interaction with pharmacological agents that can be found in drug metabolism and safety profiling effects. Microbiota-mediated drug metabolism is essential for drug discovery, which can alter the typical drug interaction with enzymes and change the efficacy level of the drug. Comprehensive investigations of microbiota–drug interactions are necessary for proper drug dosing, efficacious administration, and reduced side effects. This emphasizes the requirements of individual microbiome profiling, which would guide future personalized medicine when involving drug metabolism and toxicity. Moreover, future research should concentrate on understanding these interactions in depth and applying the knowledge to manipulate microbiota profiles so as to enhance drug response along with patient safety.