Marine mussels are constantly exposed to pathogens and have to evolve robust immune systems to recognize, tolerate and clear infections. Recent studies have highlighted the phenomenon of 'immune priming' and its role in enhanced immunity in invertebrate. Yet, there is still a lack of experimental evidence on mussels of economic value. This study investigated the potential protective effects of immune priming in hemocytes and key tissues of marine mussels (Mytilus coruscus) which were repeatedly challenged with Vibrio alginolyticus, focusing on systemic responses in survival, immune functions and antioxidant responses. The results indicated that, hemocytes, as the immune cells in mussels, initiated the immune function against Vibrio through pathogen recognition. Subsequently, toxin efflux and immune defenses were precisely regulated by promoting the inflammatory response and cell apoptosis to eliminate Vibrio and infected host cells. In parallel, antioxidant defense was coordinated to mitigate the potential oxidative stress generated during immune process. Further analysis revealed tissue-specific immune responses, with gill and digestive gland showing differential responses compared to hemocytes. Immune tolerance in gills was observed, while digestive glands exhibited sustained immune and antioxidant responses, supporting the idea that these tissues play distinct roles in maintaining homeostasis and combating pathogens. As the result, mussels in the immune-primed group exhibited slower mortality and maintained higher hemocyte viability compared to the non-primed ones, suggesting that immune priming in mussels can provide systemic protection by enhancing both cellular immunity and antioxidant defense. The results offer valuable insights into improving disease resistance in mussels' aquaculture systems.