Background/Objectives: Antimicrobial resistance (AMR) has emerged as a grave threat to human health, and a One Earth-One Health (OE-OH) concept was proposed for addressing this challenge in 2024. Here, this concept was systematically defined, clarified and refined, for better understanding it, interpreting related results, and taking some measures to combat the crisis. Methods: Using logical, reasoning and deductive methods, a dual mutation pattern was put forward for microbial resistance adhering to the principle of parsimony, integrating Lamarckian, Darwinian, and Niche construction theories, and the evolutionary origins of current AMR were schematically presented. Subsequently, its theoretical foundation, together with a fundamental mathematical model, was defined and clarified based on the robust self-regulation and perpetual reconstruction of ecosystems, and then the generation, dissemination, and elimination of AMR and antibiotic resistance genes (ARGs) were sorted out and elucidated from abiotic and biotic factors. Finally, learning from the approach of problem management, some crucial measures are suggested for the research and development, application and management of antibiotics, emphasizing the key role of simulating and utilizing the self-regulation of ecosystems. Results: A dual mutation pattern of microbial resistance and the evolutionary origins of current AMR was put forward. The theoretical foundation of the OE-OH concept, together with a fundamental mathematical model, was presented. Some unique perspectives such as AMR and ARGs emerge 3.5 billion years ago and are ubiquitous across the globe prior to antibiotic use, was clarified. Moreover, some crucial measures are proposed for addressing AMR. Conclusions: It is essential to implement the OH Joint Plan of Action from the OE-OH perspective, strongly emphasizing the key role of simulating and utilizing the self-regulation of ecosystems on addressing AMR.