<p>The rise of antimicrobial resistance (AMR) is a growing global health concern, with macrolide resistance emerging as a significant challenge due to the widespread use of these antibiotics in both clinical and non-clinical settings. While traditionally associated with healthcare environments, increasing evidence highlights the environment as a critical reservoir and dissemination pathway for macrolide resistance genes (MRGs). Environmental sources such as wastewater treatment plants (WWTPs), agricultural runoff from livestock treated with macrolides, aquaculture effluents, and pharmaceutical manufacturing discharge contribute significantly to the spread of MRGs. These anthropogenic activities introduce sub-therapeutic levels of macrolides and resistant bacteria into natural ecosystems, fostering the selection and horizontal transfer of resistance genes. Key mechanisms facilitating gene dissemination in the environment include plasmids, integrons, transposons, and bacteriophage-mediated transduction, which enable gene exchange among diverse microbial communities. Soil, surface water, sediments, biofilms, and even wildlife such as migratory birds act as persistent reservoirs and vectors, promoting regional and global spread. In response, current mitigation strategies focus on advanced wastewater treatment technologies, sustainable agricultural practices, bioremediation, and emerging tools such as CRISPR-based gene silencing. These efforts are increasingly framed within the One Health paradigm, recognizing the interconnectedness of human, animal, and environmental health. This review synthesizes the current knowledge on environmental dissemination of macrolide resistance, identifies key knowledge gaps, and highlights the need for integrated surveillance and multidisciplinary interventions.</p> Graphical Abstract <p></p>