Dynamic global vegetation models (DGVM) exhibit high uncertainty about how climate change, elevated atmospheric CO2 (atm. CO2) concentration, and atmospheric pollutants will impact carbon sequestration in forested ecosystems. Although the individual roles of these environmental factors on tree growth are understood, analyses examining their simultaneous effects are lacking. We used tree-ring isotopic data and structural equation modeling to examine the concurrent and interacting effects of water availability, atm. CO2 concentration, and SO4 and nitrogen deposition on two broadleaf tree species in a temperate mesic forest in the northeastern US. Water availability was the strongest driver of gas exchange and tree growth. Wetter conditions since the 1980s have enhanced stomatal conductance, photosynthetic assimilation rates and, to a lesser extent, tree radial growth. Increased water availability seemingly overrides responses to reduced acid deposition, CO2 fertilization, and nitrogen deposition. Our results indicate that water availability as a driver of ecosystem productivity in mesic temperate forests is not adequately represented in DGVMs, while CO2 fertilization is likely overrepresented. This study emphasizes the importance to simultaneously consider interacting climatic and biogeochemical drivers when assessing forest responses to global environmental changes.