This paper presents the development of a three-dimensional hydrodynamic-ecological model for Lake of the Woods (LoW) to assess the impact of nutrient inputs on the lake’s ecological processes. LoW is a large bi-national water body with complex geometry and topography and receives significant nutrients mainly from the Rainy River, with additional inputs from a few other smaller tributaries, and suffers from degraded water quality with seasonal cyanobacterial and harmful algal blooms. A high-resolution model developed here has a horizontal grid resolution of 250 m with a variable vertical grid resolution and can simulate hydrodynamics, in-lake nutrients dynamics, and phytoplankton biomass. Our model reproduced observed temporal and spatial distribution of nutrient and chlorophyll-a concentrations reasonably well. The calibrated model is used to explore simulating the spatial and temporal variability of ecological conditions of the lake and its response to nutrient load reductions. Based on a range of potential nutrient loadings, the model results suggest that different areas within LoW may respond differently to decreased phosphorus loadings. The model simulations predict that as nutrient loads into LoW decrease, water quality conditions will improve in most of the segments. In addition to naturally reducing internal load, external load reductions of 160 MTA from the baseline conditions (877 MTA) are necessary to reduce late summer average TP concentrations to 0.03 mg/L and total chlorophyll-a concentrations in the range of 7–12 μg/L.