Anthropogenic nutrient loading from land use, especially agriculture, is a major threat to waterbodies worldwide. Efforts to govern nutrient pollution are increasingly based on simulation modeling for research, evaluation, and regulation. This study develops a novel approach to simulate nutrient losses from agriculture applied to the Lake Champlain basin in the US state of Vermont. The Vermont Phosphorus-Index—a farm-based empirical model regularly used for site evaluation—is scaled up to the basin level with high-resolution geographic data and probabilistic estimation of unknown parameters and management practices. Results are comparable with analyses using more data and computationally intensive tools. Important insights into basin-wide management include: (1) nutrient-management planning can significantly reduce P losses in a livestock-agriculture-dominated watershed by re-distributing manure applications from areas of high loss to low loss; (2) hotspot identification from geographic data alone may be deeply complicated by high underlying heterogeneity of soil phosphorus; and (3) probabilistic modeling using simple, field-scale models is a potentially useful complement to complex watershed process models. Findings suggest that currently available best-management practices will likely be insufficient to reach reduction targets in the most impaired sub-watersheds. Reductions of agricultural land use and herd size, particularly in intensive dairy operations, may be necessary.