Background: Drug interactions play a significant role in medication errors, the key interactions are those mediated by CYP and P-gp, and most of these interactions are overlooked in a clinical setting. Objectives: This study aimed to identify the prevalence of CYP450 enzyme and P-glycoprotein-mediated drug interactions in hospitalized prescriptions, including narrow therapeutic index drugs and patients with alcohol or smoking history. Additionally, the study aimed to investigate evidence-based strategies for mitigating unintended clinically significant interactions. Materials and Methods: It is a cross-sectional observational study; the collected data are analysed for potential drug interactions using Micromedex, Drug Bank, and SuperCYP to identify which of the CYP450 enzymes and P-GP could be involved in the drug interactions, considering patients’ personal habits and medical and medication-related information. Results: A total of 196 patients had the potential for a drug interaction, but about 29 had clinically significant drug interactions. Logistic regression was performed, and all the predictor variables for PDIs were statistically significant. The most frequent drug-drug, drug-alcohol, drug-smoking, drug-food, and clinically significant interactions mediated by CYP450 and P-GP interactions were tabulated. Conclusion: Our study discusses the importance of proactively identifying preventable drug interactions. Clinical pharmacists can significantly reduce adverse outcomes and enhance patient safety by designing tailored drug regimens based on biological and pharmaceutical factors and evidence-based prescribing.