Managing forests and forest products to help mitigate climate change was quantified in three coordinated studies involving six regions within North America. Each country-specific study examined several mitigation scenarios in a comparative analysis, using harmonized tools with site-specific data and a systems approach that included forest ecosystem, harvested wood products, and substitution benefits relative to a forward-looking baseline. Here we synthesized the North American case studies by comparing normalized annual mitigation potential (net change in emissions and removals relative to the baseline), and examined differences in ecosystems and drivers that affected the ranking of mitigation activities. Considering all six study sites, the highest mitigation potential over the 32-year study period occurred in southern temperate and tropical regions where avoided deforestation, increased afforestation, and accelerated forest recovery after disturbance resulted in the greatest reduction in net emissions. The only effective scenario common to all regions was increased production of longer-lived wood products, where longer product lifetimes delayed emissions to the atmosphere, and increased substitution benefits from using wood in place of more emissions-intensive materials. We conclude that regionally differentiated mitigation scenarios that take into account diverse ecosystems dynamics and drivers offer the highest mitigation potential and a practical way to allocate resources for forestry activities.