The One Health (OH) approach, based on the interdependence of animal, human, and environmental health, presents a fruitful framework for enhancing the economic sustainability of healthcare systems. At the same time, OH proposes a new epistemology of health, and reimagines it as an emerging attribute of complex adaptive systems, determined not only by disease-causing organisms or genes, but also by land cover, biodiversity, inequality, and interspecies relationships. In this paper, in addition to the OH evolving foundations as an epistemic paradigm, we discuss the ability of OH for meeting key global challenges such as emerging infectious diseases, antimicrobial resistance (AMR), and the burden of non-communicable diseases (NCDs) using integrated, intersectoral approaches. Leveraging case studies and tools of evaluation such as the Network for Evaluation of OH (NEOH), we evaluate the cost-effectiveness and preventive benefits of OH interventions. Drawing from evidence from programs implemented in Switzerland, England, Malta, and Serbia, we describe the capacity of OH in realizing public health savings, lessening healthcare burden, and improving system effectiveness. Despite its advantages, OH is still largely neglected in health economy modeling and policy integration. We evidence key gaps in the quantification of long-term financial benefits and harmonize OH approaches with healthcare financing policies and emphasize the need of more effective cross-sector governance, uniform metrics of evaluation, and fiscal frameworks inclusive of its preventive benefits of health policies. Integrating OH into healthcare systems can enhance resilience, maximize resource allocation, and enhance preparedness for future health emergencies—goals which are core for sustainable health economics and policy design.

Keywords: One Health, health economics, cost-effectiveness, antimicrobial resistance, non-communicable diseases, healthcare sustainability, prevention.

JEL Codes: I1, H12, H41, H44, H51