Exposure to single molecules under laboratory conditions has led to a better understanding of the mechanisms of action (MeOAs) and effects of pharmaceutical active compounds (PhACs) on non-target organisms. However, not taking the co-occurrence of contaminants in the environment and their possible interactions into account may lead to underestimation of their impacts. In this study, we combined untargeted metabolomics and proteogenomics approaches to assess the mixture effects of diclofenac, carbamazepine and venlafaxine on marine mussels (Mytilus galloprovincialis). Our multi-omics approach and data fusion strategy highlighted how such xenobiotic cocktails induce important cellular changes that can be harmful to marine bivalves. This response is mainly characterized by energy metabolism disruption, fatty acid degradation, protein synthesis and degradation, and the induction of endoplasmic reticulum stress and oxidative stress. The known MeOAs and molecular signatures of PhACs were taken into consideration to gain insight into the mixture effects, thereby revealing a potential additive effect. Multi-omics approaches on mussels as sentinels offer a comprehensive overview of molecular and cellular responses triggered by exposure to contaminant mixtures, even at environmental concentrations.