The presence of macrolide antibiotics in aquatic environments has become a growing concern due to their role in promoting antimicrobial resistance. These antibiotics, frequently discharged from hospital effluents, pharmaceutical manufacturing, and agricultural runoff, persist in water systems and create favorable conditions for the selection and spread of resistant bacteria. Among the most affected species, Enterococcus faecium, Staphylococcus aureus, and Pseudomonas aeruginosa have demonstrated increasing resistance, largely driven by the horizontal transfer of ermB and msrA genes. This review examines the pathways through which macrolide contamination influences bacterial resistance and facilitates gene transmission in aquatic ecosystems. It also evaluates the effectiveness of wastewater treatment strategies, including advanced oxidation processes and membrane filtration, in mitigating antibiotic pollution. Given the rising threat of antimicrobial resistance, improving wastewater management, enforcing stricter regulations on antibiotic disposal, and enhancing monitoring systems are essential steps toward controlling the spread of resistant bacterial strains and protecting public health.