The behavior, and history of lead (Pb) contamination in the ecosystem of the Loire estuary was examined using elemental concentrations and Pb isotope data in water, sediment, bivalves, shrimps, and fish. In the estuary and in the surrounding coastal area, Pb concentrations in water and sediment decreased compared to concentrations determined in the 1980s, with concentrations ranging from 15.8 to 65.7 mg kg−1 in the surface sediment, 0.04–0.26 nM in the water column, and 48.0–77.9 mg kg−1 in suspended particles. Pb biomonitoring using blue mussels collected by the French Mussel Watch Program over the last 40 years showed a concentration decrease from 3.8 to 0.8 mg kg−1. A similar trend is observed in an estuarine sediment core. Changes in accompanying Pb isotope compositions strongly suggest a binary mixing process between Pb derived from terrigenous material and anthropogenic sources. Thus, environmental regulations restricting the release of lead into the environment contribute to a decrease in estuarine levels of this pollutant, which occurs on a decadal time scale.