Future streamflow and nutrient projections are necessary for the development of sustainable water resources management plans and practices. Watersheds located in the Northern Lake Okeechobee (NLO) areas serve as a source of water and nutrients to Lake Okeechobee and its downstream areas, including the Everglades, in South Florida. This study investigated how projected changes in climate would affect water and nutrient loading to the lake to help develop watershed management plans for improved sustainability of South Florida. Future ensemble climate projections were prepared using the outputs of 29 Coupled Model Intercomparison Project (CMIP) Phase 5 General Circulation Models (GCMs), which were then incorporated into the Watershed Assessment Model (WAM) developed to simulate the streamflow and nutrient loading from the six study drainage watersheds to the lake. The bias-corrected GCMs projected a consistent increase in air temperature in the 2040s and 2070s under both Representative Concentration Pathways (RCPs) 4.5 and 8.5 scenarios. The projected changes in precipitation substantially varied depending on the GCM selections; uncertainty in the multi-model ensemble precipitation projection was propagated to the hydrological projections. The streamflow and nutrient loading projections were closely related to the projected precipitation depths. The modeling experiment results showed that the total phosphorus loads per unit area would be consistently associated with the percentages of pastureland in both historical and future periods. Overall, nutrient loads were projected to increase. Such findings indicate the need for nutrient control strategies and innovative solutions to make progress toward Lake Okeechobee water quality goals in the face of climate change.