Coastal areas are subject to growing pressures and impacts due to increasing of the human activities. Lipophilic organic contaminants, such as polycyclic aromatic hydrocarbons (PAHs) or polychlorinated biphenyls (PCBs), have been monitored for decades within biomonitoring programs. However, until now, little information on the detection of called “emerging contaminants” as hydrophilic organic compounds, in the marine environment and no data on its metabolites or transformation products in marine organisms is available. In this way, a sensitive analytical methodology for identification and confirmation of venlafaxine residues (VEN) and five of its main metabolites in the marine mussels Mytilus galloprovincialis was validated. The sample preparation procedure was based on the Quick, Easy, Cheap, Effective, Rugged, and Safe (QuEChERS) approach. An analytical method was then developed to quantify these compounds at ultra-trace levels by liquid chromatography (LC) coupled to high-resolution mass spectrometry (HRMS). The strategy was then applied to marine mussels collected from Mediterranean Sea in southeastern France. Residues of the antidepressant VEN were occasionally detected at ng/g dw level. In addition, the approach allowed us to identify and quantify several transformation products in the analyzed samples. N-Desmethylvenlafaxine (NDV) was the most frequently detected metabolite followed by N,O-Di-Desmethylvenlafaxine (NODDV) and O-Desmethylvenlafaxine (ODV).