Antimicrobial resistance (AMR) – the ability of microbes to resist antimicrobials – remains an alarming global health threat. This is despite the efforts made by OECD and EU/EEA countries to curtail it. Unless additional effective interventions are scaled up quickly, AMR rates are forecasted to increase in the next three decades across OECD and EU/EEA countries, with costs exceeding the healthcare expenditure on the COVID-19 pandemic. Using microsimulation and machine-learning techniques, this report analyses critical policy levers to inform the next generation of AMR initiatives. It shows that tackling the detrimental health and economic impact of AMR requires embracing a One Health framework – a collaborative, trans-disciplinary and multi-sectoral approach that promotes close co-operation and collaboration across human health, animal health, agrifood systems and the environment. This report identifies 11 One Health “best buys” that, if implemented systematically, would improve population health, reduce health expenditure and generate positive returns for the economy.