The use of antibiotics in fish farming, aimed at disease prevention and control, often leads to environmental contamination, when these substances are released into the aquatic systems. This contamination exerts selective pressure on microbial populations, promoting the emergence and spread of MDR bacteria, which can subsequently transfer resistance genes to other pathogens, complicating treatment options and posing significant public health risks. Thus, there is an urgent need for alternative approaches for disease management in aquaculture, such as phage therapy, application of antimicrobial peptides, and plant-based antimicrobials. The chapter highlights the need for enhanced waste management practices and regulations to reduce the effects of antibiotic use in aquatic environments. It offers a thorough examination of these challenges and potential solutions, for mitigating antibiotic resistance and protecting both environmental and human health.