In this study, we characterize the structural variation of the microbiota of Mytilus galloprovincialis at the tissue scale, also exploring the connection with the microbial ecosystem of the surrounding water. Mussels were sampled within a farm located in the Northwestern Adriatic Sea and microbiota composition was analyzed in gills, hemolymph, digestive glands, stomach and foot by Next Generation Sequencing marker gene approach. Mussels showed a distinctive microbiota structure, with specific declinations at the tissue level. Indeed, each tissue is characterized by a distinct pattern of dominant families, reflecting a peculiar adaptation to the respective tissue niche. For instance, the microbiota of the digestive gland is characterized by Ruminococcaceae and Lachnospiraceae, being shaped to ferment complex polysaccharides of dietary origin into short-chain fatty acids, well matching the general asset of the animal gut microbiota. Conversely, the gill and hemolymph ecosystems are dominated by marine microorganisms with aerobic oxidative metabolism, consistent with the role played by these tissues as an interface with the external environment. Our findings highlight the putative importance of mussel microbiota for different aspects of host physiology, with ultimate repercussions on mussel health and productivity.