The global antibiotic resistance crisis has prompted the search for new therapeutic alternatives. In this context, the aquaculture industry has been focused on screening natural alternative sources for developing innovative therapeutics with antibacterial activity that can act as alternatives to conventional antibiotics without promoting resistance. Recently, researchers aimed to design novel strategies for infection management that reduce negative consequences for fish, humans, and aquatic ecosystems. Antimicrobial peptides (AMPs) have gained attention as potential alternatives to conventional antimicrobial agents, primarily due to their effectiveness in suppressing bacterial pathogens and, secondly, for the advantage that microorganisms are unable to develop resistance against these substances. Silkworms B. mori, as representative lepidopteran economic insects, are a promising natural source of AMPs defined as amphipathic small protein molecules, generally containing fewer than fifty amino acid residues. Most of these peptides are recognised for their immunostimulatory effects and broad-spectrum activities against various infectious and non-infectious microorganisms including bacteria, fungi, viruses, and parasites. Therefore, the synthesis and release of AMPs occur as a fundamental aspect of the innate immune defence mechanism against pathogens. In summary, this review synthesizes current knowledge on the various families of AMPs identified in silkworms, their mechanisms of action, antimicrobial properties, and the potential health benefits of AMPs as natural antimicrobial sources in aquaculture.