Between 2010 and 2021, 199 herring gull serum samples were collected from Lake Michigan, Lake Huron, and Lake Erie, including two Areas of Concern: Saginaw Bay and the River Raisin. They were analyzed for 21 polybrominated diphenyl ether congeners, 10 non-PBDE flame retardants, 85 polychlorinated biphenyls, 17 legacy organochlorine pesticides, and 36 per- and polyfluoroalkyl substances. Σ36PFAS, Σ85PCB, Σ21PBDE, and Σ17Pesticide concentrations comprised 41–74%, 17–50%, 3–4%, and 5–9% of the total concentration, respectively. Median concentrations of the chemical groups ranged from 81.5 to 129 ng/g ww for PFAS, 26.3–158 ng/g ww for PCBs, 4.26–8.89 ng/g ww for PBDEs, and 8.08–23.0 ng/g ww for pesticides. The regional concentrations of all four classes of compounds are significantly decreasing when sites are combined with halving times of 11.3 ± 4.8, 8.2 ± 4.3, 5.9 ± 3.1, and 8.3 ± 4.2 years for the Penta-BDE mixture, ΣDDTs, Σ85PCBs and Σ36PFAS, respectively. These results suggest that, while PFAS has emerged as the dominant group of chemicals in the plasma, legacy pollutants continue to represent a threat to herring gulls and wildlife in the Great Lakes basin. PCBs were the largest contributors to the chemical load in plasma of birds whose colonies are located near the River Raisin, and continue to pose a threat to herring gulls within the two Areas of Concern.