Background: Pharmacotherapy in Orthopedics often faces challenges due to patient variability in drug response. Pharmacogenomics provides insights into genetic factors that influence drug metabolism, efficacy, and toxicity, offering potential for personalized treatment plans. This study investigates the role of pharmacogenomics in optimizing Orthopaedic pharmacotherapy by tailoring drug regimens to individual genetic profiles. Objective: To assess the impact of pharmacogenomic testing on enhancing drug efficacy and minimizing adverse reactions in patients undergoing Orthopaedic treatments, with a focus on nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids commonly used for pain management. Methods: A review was conducted, including randomized controlled trials and observational studies that evaluated pharmacogenomic markers influencing drug response in Orthopaedic patients. The study used data from various genetic testing platforms to determine their relevance in predicting therapeutic outcomes and adverse drug reactions. Results: The study identified key pharmacogenomic markers such as CYP2C9, CYP2D6, and OPRM1 that significantly influence the metabolism of NSAIDs and opioids in Orthopaedic pharmacotherapy. Patients with genetic variations in these markers exhibited altered drug responses, with an increased risk of adverse effects such as gastrointestinal bleeding and opioid-induced respiratory depression. Implementing pharmacogenomic-guided therapy improved treatment outcomes by reducing adverse reactions by 30% and enhancing pain management efficacy by 25%. Conclusion: Pharmacogenomics holds significant potential for personalizing Orthopaedic pharmacotherapy, particularly in pain management. Tailoring drug regimens based on individual genetic profiles can optimize therapeutic efficacy and minimize adverse effects. Further research is needed to standardize pharmacogenomic testing in clinical practice and expand its application across a broader range of Orthopaedic treatments.