Milk exosomes contain several bioactive molecules, including lipids, proteins, and miRNAs, which enhance immune response. This study aimed to assess the resistance effects of bovine colostrum exosomes (BCEs) on pathogenic microbial infections in a Caenorhabditis elegans model. BCEs have been shown to enhance the protective response of C. elegans to pathogenic bacterial infections. Our study revealed that BCE extended the lifespan of worms compared to control OP50 worms. In addition, nematode colostrum exosomes promoted nematode resistance to four pathogenic bacteria and prolonged their lifespan in a killing assay. In contrast, mature milk-derived exosomes (BME) did not affect the resistance and lifespan of nematodes exposed to pathogenic bacteria. BCE exposure extended the lifespan of C. elegans against pathogenic infections by stimulating the innate immune response and increasing antimicrobial protein expression. Using biological process-related gene ontology (GO) enrichment analysis, the significantly upregulated GO terms related to C. elegans immunity in BCE-exposed C. elegans included defense, innate immunity, and immune responses. This study demonstrated that BCE enhanced the host defense of C. elegans to prolong its lifespan, thereby suggesting a new natural product against infection by pathogenic bacteria.