The application of zinc (Zn) isotope compositions in bivalve organisms to quantify anthropogenic Zn bioaccumulation in marine biota is of great interest to environmental marine management programs such as the “Mussel Watch Program”. Field studies, however, are urgently needed to test its practical value. To this end, we investigated Zn isotope variations in the oyster Crassostrea gigas collected over four decades near the Loire estuary (France), where previous geochemical studies provided evidence for a regionally uniform but temporally variable metal contamination. We show that the Zn temporal isotope profile of oysters matches that of the sedimentary records with an isotope offset of approximately +0.5–0.7‰, tentatively attributed to compromised estuarine processes and trophic transfer. A Zn isotope model for quantifying anthropogenic Zn bioaccumulation suggests an overall decrease in anthropogenic estuarine Zn levels over the past 40 years. This first successful application of Zn isotope ratios in a bivalve species to quantify anthropogenic Zn bioaccumulation confirms their utility for supporting environmental management strategies in marine biomonitoring programs.