Several important environmental influences of tree growth and carbon sequestration have changed over the past several decades in eastern North America, specifically, more frequent pluvial conditions, increased carbon dioxide (CO2) concentrations, and decreased acidic deposition. These factors could lead to changes in the relationship between tree growth and water availability, and perhaps even decouple the two, having large implications on how future climate change will impact forest productivity and carbon sequestration. Here, we examine the concurrent influence of the climatic water balance (precipitation minus potential evapotranspiration), CO2 concentrations, and sulfate and nitrogen deposition on radial tree growth, carbon isotopes, and intrinsic water-use efficiency (iWUE) for several hardwood tree species in the Midwestern United States. We found that when considering the simultaneous influence of these factors, the climatic water balance is the dominant influence on annual growth. Therefore, the recent pluvial period is the primary cause of the weakening relationship between radial growth and water availability. Even during pluvial periods, water availability is the primary control on growth, with increasing CO2 concentrations and decreased SO4 deposition being secondary factors. Importantly, the weakening in the climate-growth relationship is species specific, with Acer species having stable relationships with the climatic water balance, Liriodendron tulipifera showing a strengthening relationship, and Quercus species and Populus grandidentata exhibiting weakening. Thus, interannual variations in soil moisture unevenly impact tree growth and carbon sequestration. Our findings suggest that, despite recent pluvial conditions, increasing CO2 concentrations and decreasing acidic deposition have not buffered the impact of water availability on tree growth and carbon sequestration.