Temperate forests regrowing from historical land use and land cover change in the eastern US serve as carbon (C) sinks. Environmental drivers have been significantly altered (e.g. rising atmospheric CO2 concentration, warmer temperature, and elevated nitrogen (N) deposition) and will have a wide range of impacts on future forest C sinks. However, the interactions among these environmental drivers are unclear and their effects are subject to uncertainty. We assessed the combined and interactive effects of rising CO2 concentration, climate change (temperature, precipitation), and N deposition on forest aboveground net primary production (ANPP) and their relative contribution to ANPP changes of a temperate forest in the eastern US. We used a process-based ecosystem model PnET-day to simulate coupled cycles of C, water, and N of forest ecosystems. We found that (1) climate change exerted negative effects on ANPP (−0.250 kg C m−2 yr−1) whereas rising CO2 and N deposition enhanced ANPP (+0.253, +0.014 kg C m−2 yr−1); (2) climate change interacted with rising CO2 and N deposition to decrease ANPP (−0.032, −0.018 kg C m−2 yr−1); rising CO2 and N deposition acted in synergy to increase ANPP (+0.014 kg C m−2 yr−1); (3) changes in ANPP were mainly attributed to rising CO2 and climate change whereas N deposition effects and any two- or three-factor interactive effects were relatively small. Our results suggest that the total negative effect sizes will not be offset by the total positive effect sizes, thus resulting in reductions in forest ANPP over the 21st century.