Aquaculture faces significant challenges due to bacterial infections, particularly , leading to extensive antibiotic use and raising concerns about antimicrobial resistance. In this context, bacteriophages and bacterial defense systems play a critical role in the evolutionary dynamics of . This study aimed to investigate the genomic landscape of prophage regions and antiphage defense systems in Piscirickettsia salmonis to better understand their co-evolutionary dynamics and explore their potential role in alternative disease control strategies for aquaculture. We analyzed 79 genomes of using bioinformatic tools to identify and characterize prophage regions and antiphage defense systems. At the chromosomal level, 70% of the strains contained prophage regions, with a total of 92 identified regions, most of which were classified as intact. At the plasmid level, 75% of plasmids carried prophage regions, with a total of 426 identified regions, predominantly associated with , , and . Prophage regions were enriched in transposases, head proteins, tail proteins, and phage-like proteins. The analysis of antiphage defense systems revealed that predominantly harbors dGTPase, AbidD, and SoFIC at the chromosomal level, whereas MazEF was the most frequent system in plasmids. A strong positive correlation was found between the number of prophage regions and defense systems in chromosomes (ρ = 0.72, = 6.3 × 10), while a weaker correlation was observed in plasmids. These findings highlight the complex interplay between and its bacteriophages, with implications for disease control in aquaculture. Overall, these insights into the prophage and defense system dynamics provide potential avenues for developing alternative strategies to combat infections and reduce reliance on antibiotics in aquaculture systems.