Introduction: Fixed Dose Combinations (FDCs) play a crucial role in pharmaceuticals by incorporating multiple approved Active Pharmaceutical Ingredients (APIs) into a single dose. The intent is to enhance medication adherence, reduce poly-pharmacy, and promote cost-effectiveness. While the World Health Organization's Seventeenth Model List of Essential Medicines (March 2011) includes only 25 approved FDCs, India's National Essential Medicines List encompasses 354 essential medicines, featuring 14 FDCs. However, the irrational use of FDCs poses significant risks, leading to adverse effects, therapeutic failure, ineffective dosing, susceptibility to abuse, and increased costs. Identifying the causes of such side effects becomes challenging with FDCs, making a critical examination imperative. Objective: The primary objective of this study is to examine and discuss the irrationality of selected FDCs available in the market. Methodology: This study focuses on the irrationality of selected FDCs available in the market, including combinations such as Ramipril and Telmisartan, Aspirin and Clopidogrel, Rosuvastatin and Fenofibrate, Fluoxetine and Alprazolam, Amitriptyline and Chlordiazepoxide, Lovastatin and Nicotinic acid, Isoniazid and Rifampicin, Isoniazid and Ethambutol, Zidovudine and Lamivudine, Chlorpromazine and Trihexyphenidyl and Trifluoperazine, Domperidone and Rabeprazole, Atorvastatin and Amlodipine, Ezetimibe and Atorvastatin, Atenolol and Nifedipine, Salbutamol and Theophylline, Salbutamol and Ipratropium bromide, indicated for various diseases. The rationality of these FDCs is analyzed using authoritative resources such as AHFS drug information, BNF, Martindale: The complete drug reference, Stockley’s drug interactions, among others. Results: The analysis reveals that the irrational use of FDCs may lead to adverse consequences, with potential risks such as side effects, therapeutic failure, and increased costs. By scrutinizing specific FDCs, including Ramipril and Telmisartan, Aspirin and Clopidogrel, Rosuvastatin and Fenofibrate, among others, evidence from authenticated resources is used to assess their rationality. Continuous monitoring and periodic clinical studies are deemed essential to justify the rationality of these FDCs, ensuring their safety and efficacy. Conclusion: In conclusion, the study underscores the need for a critical evaluation of FDCs to ensure their rational use in clinical practice. The presence of numerous FDCs in the market demands continuous monitoring and periodic clinical studies to validate their safety, efficacy, and cost-effectiveness. The results emphasize the importance of evidence-based assessments from authoritative drug information sources to guide healthcare professionals and policymakers in promoting rational FDC prescribing practices.