The Ecosystem Demography (ED) model was parameterized with ecological, forest inventory, and historical land use observations in an intensively managed, wetland-rich forested landscape in the upper midwest United States. Model results were evaluated against a regional network of eddy covariance flux towers and analyzed about the roles of disturbance, forest management, and CO2 fertilization. The model captured modern regional vegetation structure with worst comparison in wetlands. Model net ecosystem exchange of CO2 (NEE) was highly correlated on monthly (r2 = 0.65) and annual (r2 = 0.53) timescales to 7 years of NEE observed at a 396-m-tall eddy covariance (EC) tower and to 2 years of growing season NEE from 13 regional stand-scale EC sites of varying cover and age (r2 = 0.64). Model summer NEE had higher than observed net uptake for the tall tower and mature hardwood sites, and correlation to growing season ecosystem respiration at these sites was poor (r2 = 0.09). Exclusion of forestry led to overestimation of aboveground living plant biomass accumulation by 109% between two forest inventory cycles (1996-2004). On the long-term (200 years), forestry significantly altered ecosystem cover and age, and increased NEE by 32%. CO2 fertilization over that time period increased NEE by 93% owing to a doubling of plant density. While the model showed that harvest and afforestation had smaller impacts on NEE than CO2 increase, the former were still significant and require consideration when making future NEE predictions or scaling plot-level data to regional and global flux estimates.