Drug-drug interactions (DDI) are the most common cases that occur in our healthcare in which are very alarming as it may lead to severe complications. Consumption of natural products concomitantly with conventional drugs or treatment using polypharmacy have become the norm that promoting the potential of pharmacokinetic or pharmacodynamic drug interactions as the combination may mimic, increase or reduce the effects of the drug or the herb which could result in clinically significant interactions. CYP2C9 is the second major isoform from CYP450 family of enzyme, which responsible in phase 1 metabolism of 15-20% clinical drugs. Up to date, many substrates of CYP2C9 have been discovered and these discoveries may open more doors for potential drug-drug interactions in patients. Many studies have been done to evaluate the effect of drugs on the activity of CYP2C9 and how it influenced the effectiveness of therapy in patients. Various data regarding CYP2C9 related DDI from in vitro, in vivo and clinical studies were critically discussed in this review to provide insights on how these drugs and natural products may exhibit drug interactions clinically. This review could be beneficial reference material for health practitioners and researchers.