Aquaculture has traditionally relied on antimicrobial agents, particularly antibiotics, to prevent and treat bacterial infections. However, the overuse of antibiotics has led to the emergence of antibiotic-resistant bacteria, posing significant threats to both animal and human health. Consequently, there is a growing shift towards alternative antimicrobial strategies to ensure sustainable and effective disease management in aquaculture. Key alternatives include probiotics, vaccines, bacteriophages, plant extracts, and antimicrobial peptides (AMPs). Probiotics enhance gut health and immune response, reducing disease incidence and promoting growth in aquatic animals. The vaccines provide specific, long-lasting protection against pathogens, thereby minimizing the need for antibiotics. Bacteriophages specifically target and destroy bacteria and offer a precise method of bacterial control without disrupting beneficial microbiota. Plant extracts, with their natural antimicrobial properties, serve as effective agents in preventing infections and enhancing overall health. Antimicrobial peptides represent a significant advancement in combating pathogens in aquaculture. These naturally occurring molecules exhibit broad-spectrum activity against bacteria, fungi, and viruses, serving as a highly effective strategy for disease management. This chapter examines the mechanisms, benefits, and limitations of these antimicrobial strategies, highlighting their critical role in addressing the challenges posed by antibiotic resistance. We emphasize their pivotal role in tackling the challenges of antibiotic resistance and highlight the significance of incorporating these innovative approaches to foster a more resilient and sustainable aquaculture practices.