Rising atmospheric CO 2 (c a) is expected to promote tree growth and lower water loss via changes in leaf gas exchange. However, uncertainties remain if gas-exchange regulation strategies are homeostatic or dynamical in response to increasing c a , as well as evolving climate and pollution inputs. Using a suite of tree ring-based δ 13 C-derived physiological parameters (Δ 13 C, c i , iWUE) and tree growth from a mesic, low elevation stand of canopy-dominant Tsuga canadensis in northeastern USA, we investigated the influence of rising c a , climate and pollution on, and characterised the dynamical regulation strategy of, leaf gas exchange at multidecadal scales. Isotopic and growth time series revealed an evolving physiological response in which the species shifted its leaf gas-exchange strategy dynamically (constant c i ; constant c i /c a ; constant c a − c i) in response to rising c a , moisture availability and site conditions over 111 yr. Tree iWUE plateaued after 1975, driven by greater moisture availability and a changing soil biogeochemistry that may have impaired a stomatal response. Results suggested that trees may exhibit more complex physiological responses to the changing environmental conditions over multidecadal periods, and complicating the parameterisation of Earth system models and the estimation of future carbon sink capacity and water balance in midlatitude forests and elsewhere.