Octopus maya is an endemic species of high ecological and socioeconomic importance in the Yucatán Peninsula, representing the fourth most valuable fishery in Mexico and the most important cephalopod fishery in the country. Recent findings have revealed that this species can develop a parasitic disease associated with cestodes of the genus Prochristianella, representing a previously undescribed pathology in mollusks. An integrative methodological approach was applied to characterize the effects of natural infections caused by Prochristianella sp. 1 in the buccal mass of O. maya. Morphological and molecular tools were used to confirm the identity of the parasite, while macroscopic and histological assessments were used to assess tissue damage and hemocyte responses in infected versus uninfected individuals of O. maya. Immune-related genes were analyzed to explore potential molecular responses associated with infection. This combined strategy provided a comprehensive understanding of the pathological process and host–parasite interaction from cellular to organismal levels. High-intensity infections resulted in progressive tissue degradation of the superior mandibular muscle, accompanied by increased hemocyte counts and histopathological alterations consistent with an inflammatory response. The expression of immune-related genes was evaluated. Gene C1q, associated with the complement system, and LITAF, a regulator of tumor necrosis factor α, were significantly overexpressed in infected individuals, suggesting activation of both immune and pro-inflammatory pathways. The pathology, provisionally named Myocestodiasis in cephalopods, represents a novel helminth disease. These findings emphasize the importance of addressing host–parasite interactions in marine invertebrates through a One Health perspective, recognizing the interconnectedness between environmental health, animal health, and human well-being. By identifying a new parasitic disease in a species of economic relevance, this study provides essential insights for monitoring the sanitary status of wild octopus populations and underscores the need to integrate parasitological, ecological, and immunological information to ensure the sustainability of fisheries in the Yucatán Peninsula.