During the 1970s, harmful cyanobacteria (HFCB) were common occurrences in western Lake Erie. Remediation strategies reduced total P loads and bloom frequency; however, HFCB have reoccurred since the mid-1990s under increased system stress from climate change. Given these concurrent changes in nutrient loading and climate forcing, there is a need to develop management tools to investigate historical changes in the lake and predict future water quality. Herein, we applied coupled one-dimensional hydrodynamic and biogeochemical models (GLM–AED) to reproduce water quality conditions of western Lake Erie from 1979 through 2015, thereby removing the obstacle of setting and scaling initial conditions in management scenarios. The physical forcing was derived from surface buoys, airports, and land-based stations. Nutrient loads were reconstructed from historical monitoring data. The root-mean-square errors between simulations and observations for water levels (0.36 m), surface water temperature (2.5 °C), and concentrations of total P (0.01 mg L−1), PO4 (0.01 mg L−1), NH4 (0.03 mg L−1), NO3 (0.68 mg L−1), total chlorophyll a (18.74 μg L−1), chlorophytes (3.94 μg L−1), cyanobacteria (12.44 μg L−1), diatoms (3.17 μg L−1), and cryptophytes (3.18 μg L−1) were minimized using model-independent parameter estimation, and were within literature ranges from single year three-dimensional simulations. A sensitivity analysis shows that 40% reductions of total P and dissolved reactive P loads would have been necessary to bring blooms under the mild threshold (9600 MTA cyanobacteria biomass) during recent years (2005–2015), consistent with the Annex 4 recommendation. However, these would not likely be achieved by applying best management practices in the Maumee River watershed.