Veterinary medicines may be used appropriately or inappropriately in animal health care. Misuse of these drugs represents a major challenge in modern veterinary practice, resulting in medication-related problems, treatment failures, and increasing risks to animal, human, and environmental health, as well as higher drug expenditures. These challenges arise from administering drugs to cases not requiring treatment, prescribing or dispensing unsafe products, and improper drug use by animal owners. Irrational drug use remains a major concern in many developing nations, including Ethiopia, where veterinary drug prescriptions are commonly based on tentative diagnosis in clinics. Limited availability of veterinary pharmaceuticals, weak regulatory enforcement, and poor access to drug information also drive misuse. Studies from Ethiopia have documented illegal drug vendors operating under poor conditions and a high incidence of irrational drug use and its contributing factors. The most alarming consequence of misuse is antimicrobial resistance, a serious threat to both human and animal health. Evidence shows that antimicrobial resistance generated from animal sources significantly contributes to the wider AMR problem, in combination with human and environmental factors. Continued irrational circulation of veterinary pharmaceuticals poses future threats to global human, animal, and environmental health. Accordingly, the World Health Organization has adopted a multisectoral One Health strategy to address irrational drug use and antimicrobial resistance, although implementation emerged late. Another critical public health issue is drug residue in food animals. High levels of antimicrobial residues in meat, milk, eggs, and organs are strongly linked to misuse of veterinary medicines. These consequences also bring economic burdens through increased treatment costs, livestock mortality, reduced productivity, and loss of income for vulnerable farmers. Therefore, minimizing irrational veterinary drug use and its repercussions requires strengthened regulatory oversight and promotion of rational drug utilization.