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.