Forests provide several critical ecosystem services that help to support human society. Alteration of forest infrastructure by changes in land use, atmospheric chemistry, and climate change influence the ability of forests to provide these ecosystem services and their sensitivity to existing and future extreme climate events. Here, we explore how the evolving forest infrastructure of the Midwest and Northeast United States influences carbon sequestration, biomass increment (i.e., change in vegetation carbon), biomass burning associated with fuelwood and slash removal, the creation of wood products, and runoff between 1980 and 2019 within the context of changing environmental conditions and extreme climate events using a coupled modeling and assessment framework. For the 40-year study period, the region’s forests functioned as a net atmospheric carbon sink of 687 Tg C with similar amounts of carbon sequestered in the Midwest and the Northeast. Most of the carbon has been sequestered in vegetation (+771 Tg C) with more carbon stored in Midwestern trees than in Northeastern trees to provide a larger resource for potential wood products in the future. Runoff from forests has also provided 4,651 billion m3 of water for potential use by humans during the study period with the Northeastern forests providing about 2.4 times more water than the Midwestern forests. Our analyses indicate that climate variability, as particularly influenced by heat waves, has the dominant effect on the ability of forest ecosystems to sequester atmospheric CO2 to mitigate climate change, create new wood biomass for future fuel and wood products, and provide runoff for potential human use. Forest carbon sequestration and biomass increment appear to be more sensitive to heat waves in the Midwest than the Northeast while forest runoff appears to be more sensitive in the Northeast than the Midwest. Land-use change, driven by expanding suburban areas and cropland abandonment, has enhanced the detrimental heat-wave effects in Midwestern forests over time, but moderated these effects in Northeastern forests. When developing climate stabilization, energy production and water security policies, it will be important to consider how evolving forest infrastructure modifies ecosystem services and their responses to extreme climate events over time.