The Pacific oyster faces significant threats from recurring outbreaks of Pacific Oyster Mortality Syndrome (POMS), a polymicrobial and multifactorial disease. Recent researches have underscored the crucial role of epigenetics in shaping oyster resistance and susceptibility through microevolutionary pressures. We conducted a comprehensive characterization of the basal (no infection) and the POMS-induced changes of the methylome in resistant and susceptible oysters focusing on the gills and mantle. Our analysis identified differentially methylated regions (DMRs), which revealed distinct methylation patterns uniquely associated with either susceptible or resistant phenotypes in each tissue. Enrichment analysis of the methylated genes highlighted that these epigenetic changes were specifically linked to immunity, signaling, metabolism, and transport. Notably, among the methylated genes, and regardless of the tissue, 31 genes with well-known immune responses were differently methylated after POMS with contrasted methylation between phenotypes. This suggests that epigenetic changes can also drive rapid adaption, enabling oyster populations to develop enhanced resistance to POMS diseases through heritable, yet environmentally influenced induced changes. We hypothesized that these epigenetic changes during POMS infection may result from a negative feedback loop between transcription and methylation, viral manipulation of host cellular machinery, or interactions between these mechanisms. Additionally, and beyond its biological aspect, this study provided insights into potential epigenetic biomarkers for POMS disease management and targets for enhancing oyster health and productivity. Based on the substantial methylome differences between phenotypes, we identified a set of candidate epibiomarkers that could characterize whether an oyster is resistant or susceptible (1,998 candidates) and whether a site has been exposed to POMS or not (164 candidates). Overall, the findings provide a deeper understanding of the molecular interactions between oysters and POMS infection opening new questions about the broader implications of epigenetic mechanisms in host-pathogen dynamics and offering promising strategies for mitigating the impacts of this devastating disease.