Heavy metal accumulation in marine sediments is associated with changes in both the natural environment and human activities. This study used heavy metals and Pb isotopes in a precisely dated (by 210Pb and 137Cs) sediment core from the Macao Sea to reconstruct the historical changes in anthropogenic activities and the environment in the western Pearl River Estuary (PRE). The distribution of heavy metals in the sediment core could be divided into four stages (pre-1950, 1950–1976, 1976–2000, and post-2000), which corresponded to the changes in anthropogenic activities and environment of the Pearl River Delta during the past 100 years. The contribution of anthropogenic metals (Pb and Zn) in the sediments increased gradually over time. However, the concentrations, enrichment factors, and fluxes of heavy metals in the sediments all displayed a downward trend since 2010, revealing a decline in metal pollutant input due to strict emission reduction policies implemented in the last decade. The Pb isotopes in the sediments showed a similar trajectory to the heavy metals, reflecting the changes in Pb sources in the sediments at different stages. Based on a binary Pb isotope mixing model, the calculated proportions of anthropogenic and natural Pb in the sediments were 0–50.9% (mean 15.9%) and 49.1–100% (mean 84.1%), respectively, suggesting that the Pb in the PRE sediments is mainly controlled by natural sources.