Antimicrobial resistance (AMR) represents a major One Health issue, driven by a myriad of potential accelerators that include emerging climate and social challenges. There is little doubt about the need for interventions at critical control points to reduce AMR, but addressing AMR within a single realm of One Health (for example, human, animal or environmental) is not sufficient to reduce it. Building on the past decade of research, this Perspective highlights comprehensive, systemic and integrative strategies that address the effects of anthropogenic activities and the complex relationship between humans and the environment as key targets for intersectoral and global action.