Rational use of medicines (RUM) is a cornerstone of safe, effective, and affordable health care. In Nepal, irrational medicine use-particularly of antibiotics-remains widespread, driven by self-medication, over-the-counter (OTC) sales without prescription, inappropriate prescribing practices, weak regulatory enforcement, and commercial influences. These practices contribute directly to the growing burden of antimicrobial resistance, increased adverse drug reactions (ADR), and avoidable economic costs for households and the health system. This perspective article synthesizes recent evidence from knowledge, attitude, and practice (KAP) studies, national policy experiences, and global trends from the past five years to examine the magnitude and drivers of irrational medicine use in Nepal. Ensuring RUM is a shared responsibility involving individuals, communities, health professionals, regulators, policymakers, pharmaceutical industries, and the media. Strengthening RUM in Nepal requires coordinated regulatory enforcement, antimicrobial stewardship, and community-level behavior change.