A significant consequence of antibiotic use is the rise in antimicrobial resistance (AMR), which complicates the treatment of common bacterial diseases in aquatic organisms. Furthermore, antibiotic residues in food fish and their products can lead to export rejections and negatively impact global trade. To address these issues, good aquaculture practices and effective biosecurity measures should incorporate antibiotic alternatives alongside cautious and responsible antibiotic use to reduce the prevalence of antibiotic-resistant bacteria. This chapter explores the use of antibiotics and the increase in AMR in aquaculture, while also discussing viable alternatives, including antivirulent therapy, quorum-sensing inhibitors, vaccination, bacteriophages, nanomedicine, monoclonal antibody (mAb) therapy, phage therapeutics, antimicrobial peptides (AMPs), and medicinal plant derivatives.