<p>Antimicrobial resistance (AMR) represents one of the most pressing global health and ecological challenges of the twenty-first century. Resistant organisms and genes move freely across humans, animals, food systems, and the environment, with wastewater, soil, and wildlife acting as critical reservoirs. This interconnectedness highlights the need for a coordinated One Health framework that recognises AMR as both a medical and ecological crisis. In this review, we examine the mechanisms driving the emergence and dissemination of AMR and explore how stewardship, ecological management, and policy interventions can be integrated to mitigate its spread. We particularly consider how selective pressures operating across clinical and environmental settings influence resistance persistence and transmission. Evidence shows that judicious antimicrobial use in healthcare and veterinary medicine, coupled with environmental safeguards such as wastewater management and effluent regulation, can reduce selective pressure and transmission risk. Case studies illustrate how coordinated surveillance across sectors provides early warning of emerging resistomes, while stewardship programmes prolong the efficacy of existing antibiotics. Together, these findings highlight the importance of integrated responses that address resistance across interconnected human, animal, and environmental systems. By situating AMR within the broader human–animal–environment interface, this review underscores the critical importance of ecological thinking in designing sustainable solutions. Embedding One Health principles into global and national action plans is essential to safeguard biodiversity, strengthen resilience, and preserve the effectiveness of antimicrobials for future generations.</p> Graphical Abstract <p></p>