To help reduce future N loads entering the Gulf of Mexico from the Mississippi River 45%, Iowa set the goal of reducing non-point source N loads 41%. Studies show that implementing winter rye cover crops into agricultural systems reduces N loads from subsurface drainage, but its effectiveness in the Mississippi River Basin under expected climate change is uncertain. We used the field-tested Root Zone Water Quality Model (RZWQM) to estimate drainage N loads, crop yield, and rye growth in central Iowa corn-soybean rotations. RZWQM scenarios included baseline (BL) observed weather (1991–2011) and ambient CO2 with cover crop and no cover crop treatments (BL_CC and BL_NCC). Scenarios also included projected future temperature and precipitation change (2065–2085) from six general circulation models (GCMs) and elevated CO2 with cover crop and no cover crop treatments (CC and NCC). Average annual drainage N loads under NCC, BL_NCC, CC and BL_CC were 63.6, 47.5, 17.0, and 18.9 kg N ha−1. Winter rye cover crop was more effective at reducing drainage N losses under climate change than under baseline conditions (73 and 60% for future and baseline climate), mostly because the projected temperatures and atmospheric CO2 resulted in greater rye growth and crop N uptake. Annual CC drainage N loads were reduced compared with BL_NCC more than the targeted 41% for 18 to 20 years of the 21-year simulation, depending on the GCM. Under projected climate change, average annual simulated crop yield differences between scenarios with and without winter rye were approximately 0.1 Mg ha−1. These results suggest that implementing winter rye cover crop in a corn-soybean rotation effectively addresses the goal of drainage N load reduction under climate change in a northern Mississippi River Basin agricultural system without affecting cash crop production.