The global increase in seafood consumption has boosted aquaculture and fish production, supplying 17% of the world’s animal protein. However, rising demand has raised concerns about excessive antimicrobial use in aquaculture, reaching 63,151 tons globally in 2010 and is projected to increase by 67% by 2030. The chapter examines antibiotic-resistant bacteria in aquaculture, explores public health implications, and offers recommendations. Widespread use of antimicrobial agents, including critical ones, in major fish-producing countries poses risks to public health and the environment. The complex issue involves the excretion of significant amounts of antimicrobial agents into the environment, contributing to antibiotic resistance. Challenges to food safety in aquaculture include antibiotic residue and antibiotic-resistant bacteria. Scientifically sound management practices, biosecurity measures, and alternative approaches like immunostimulants and vaccines are crucial. Strengthening regulatory frameworks and promoting sustainable practices are essential for ensuring the safety of aquaculture products and addressing global antimicrobial resistance. Future research and actions are needed to tackle critical challenges and adopt holistic strategies in aquaculture.