Rational use of medicines (RUM) ensures patients receive appropriate medications at the right dose, frequency, and duration. This study evaluated RUM in hospitalized adults at a multi-specialty hospital in Chennai, India. An inpatient cohort was screened for RUM compliance. Patient demographics, medical history, medications, and laboratory data were collected. Medications were assessed for rationality using standard guidelines and WHO prescribing core indicators. Gastrointestinal medications were the most irrationally prescribed, followed by antimicrobials and CNS agents. The most common irrationalities were drug use without proper indication, wrong drug selection, and incorrect dosing frequency. Polypharmacy and fixed-dose combinations (FDCs) negatively impacted prescription rationality. WHO core indicators revealed an average of 7 medications per prescription, exceeding the optimal range. This study identified a high prevalence of irrational medication use, particularly in the gastrointestinal category. Polypharmacy and FDCs contributed to these issues. Regular prescription audits and improved patient interactions are essential to promote RUM in hospital settings.