In a context of increasing global levels of marine pollution, it is necessary to develop more efficient control strategies, implementing sustainable biomonitoring and remediation approaches, which allow to protect and restore the most impacted habitats. Marine mussels, especially Mytilus galloprovincialis, is as well-established sentinel species, due to their vast distribution, their role at the base of trophic chains and their filter feeding strategies. However, the role of the mussel-associated microbiome in the animal response to environmental pollution is poorly explored, despite its potential in xenobiotic detoxification and its important role in host development, protection, and adaptation. Here, we characterized the microbiome-host integrative response of M. galloprovincialis in a real-world setting, involving exposure to a complex pattern of emerging pollutants, as occurs in the Northwestern Adriatic Sea. A total of 387 mussel individuals from 3 commercial farms, spanning about 200 km along the Northwestern Adriatic coast, and in 3 different seasons, were collected. Multiresidue analysis (for quantitative xenobiotic determination), transcriptomics (for host physiological response), and metagenomics (for host-associated microbial taxonomical and functional features) analyses were performed on the digestive glands. M. galloprovincialis responds to the presence of the complex pattern of multiple emerging pollutants detected in summer – including the antibiotics sulfamethoxazole, erythromycin, and tetracycline, the herbicides atrazine and metolachlor, and the insecticide N,N-diethyl-m-toluamide – integrating host defense mechanisms, e.g., through upregulation of transcripts involved in animal metabolic activity, and of genes related to microbiome-mediated detoxification functions, including genes for multidrug or tetracycline resistance. Overall, our data highlight the importance of mussels as biomonitoring systems, with the associated microbiome representing the most sensitive counterpart, but also showing animal potential in resistance and, ultimately, detoxification of emerging pollutants in a context of high anthropogenic pressure.