Forest carbon (C) sequestration in the eastern US will largely be driven by the interactive effects of disturbance due to land use change or management, climate, elevated CO2, and air pollution during the 21st century. In this study, we parameterized a process-based model (TEM-Hydro2) to quantify the effects of agriculture and timber harvest, climate, elevated CO2, and ozone on C sequestration during the 20th and the 21st century. We have not included the effects of natural disturbance such as fire, insect outbreaks, hurricanes, and tropical storms during the course of this study. Our site-specific comparisons suggest that C recovery of forests after anthropogenic disturbance depends on the time since disturbance and amount of C in different pools, including wood product pools with residence times ranging from 1 to 100 years. Our 20th century regional simulations show that recovery following anthropogenic disturbance and elevated CO2 increased net carbon exchange (NCE), or net gain in the sink strength, by 64 and 32%, respectively, while ozone decreased NCE by 18%. However, there was a net loss of C due to disturbance if accounting from 1700. The 21st century simulation using the SRES A2 emissions resulted in an increase in NCE by 79% following partial annual timber harvest and 31% due to CO2 fertilization, whereas climate and ozone decreased NCE by 12 and 8%, respectively. Our modeling results indicate that anthropogenic disturbance is an important factor to include for improving model accuracy in simulating C stocks and fluxes of eastern temperate forests.