The variegated scallop (Mimachlamys varia) is a filter feeder bivalve encountered in marine regions of the Atlantic coast. In particular, it is present in the La Rochelle marina (France), where it is used for the biomonitoring of marine pollution, due to its ability to strongly bioaccumulate pollutants. In this semi-closed environment, contamination generated by port activities leads to an accumulation of both organic and metal pollutants. Zinc is one of these pollutants, present at a dose of up to 150 μg.L−1. This study investigated the effects of 48 h zinc exposure upon the metabolic profiles of Mimachlamys varia using UHPLC/QToF (ultra-high performance liquid chromatography-quadrupole time-of-flight) tandem mass spectrometry metabolomics. After acclimation in mesocosms recreating in situ conditions, both controls and exposed with Zn2+ (150 μg.L−1) bivalves were dissected to recover the gills after 48 h and stored at −80 °C before metabolites extraction. UHPLC/QToF tandem mass spectrometry was performed to study metabolite composition of samples. Statistical analysis of results using multivariate techniques showed a good classification between control and exposed groups. Eleven identified metabolites were found to be down-modulated in exposed scallops. These variations could reflect potential zinc effects on several of the biological processes, such as energy metabolism, osmoregulation and defense against oxidative stress. Among the eleven metabolites highlighted, four were reported for the first time in an aquatic organism exposed to Zn. This study demonstrates once again the diversity of interactions between bivalves and metals and the complexity of the physiological response of marine bivalves to pollutants.