Antimicrobial resistance (AMR) is a complex One Health problem involving people, non-human species, and the environment. This review examines the distribution and transmission of multidrug-resistant (MDR) bacteria and antibiotic resistance genes (ARGs) across these domains. One Health has broken the long-standing isolation of MDR research by establishing a unified cross-disciplinary analytical framework, supporting interdisciplinary MDR studies, and systematically mapping the complete transmission chains and pathways of MDR determinants (including drug-resistant pathogens and resistance genes) at the human–animal–environment interface. This holistic perspective has become an indispensable guiding principle for addressing complex global health challenges.