Drug metabolism studies play a critical role in the optimization of the therapeutic efficacy of newer drug candidates. Many drug candidates and drugs were withdrawn from the pre-clinical/clinical-stage or market due to the poor metabolic profiles. The poor metabolic profiles may make the clinical candidates/drugs inactive or toxic. Therefore, it is necessary to optimize the metabolic profiles at the initial phase of drug discovery and development processes. Recently, molecular modeling approaches were found to be useful in the optimization of metabolic profiles of clinical candidates. The molecular modeling approaches were employed in the identification of various metabolic profiles. In the present study, the current status of the research work on drug metabolism based on molecular modeling methodologies has been reviewed. The basics of drug metabolism and its importance in the physiological process of the human body have been described. Moreover, the involvement of molecular modeling approaches like pharmacophore-based modeling, QSAR, molecular docking, virtual screening, quantum chemical analysis, molecular dynamics, etc in predicting metabolic profiles of therapeutic agents is analyzed. The present review provides computational insights in the prediction of substrate specificity, metabolic activity, SOM, metabolites, toxicity, etc. on cytochrome P450 mediated drug metabolism. The study may help the researchers to design novel drug candidates for the various classes of therapeutic targets with efficient metabolic profiles.