This study evaluates the transcriptional profiles of genes related to physiological responses in digestive glands (DG) of Mytilus galloprovincialis under the influence of natural seasonal changes of environmental variables, gender bias, and gonadal development. Composition of the mussel DG microbiome was also explored. Mussels were collected across 6-months encompassing 3 seasons from a farm in the Northwestern Adriatic Sea. All gene products showed complex transcriptional patterns across seasons. Whether in females temperature and gonadal maturation mostly explained the observed transcriptional changes, salinity, surface oxygen and transparency significantly affected transcriptional profiles of males. Seasonal variations and gender-specific differences were further observed in DG microbioma composition, suggesting adaptive variations putatively matching host physiological changes, particularly those addressing metabolic accommodations related to season progression and reproductive cycle. Results show the utility of an integrative approach combining mussel transcriptome and microbiome data to address holobiont health status as affected by the complex natural systems.