Applying an interaction framework, we examined whether climate change and combined land use and disturbance changes were synergistic, antagonistic, or neutral for forest issues of wildfires, tree growth, tree species distributions, species invasions and outbreaks, and deer herbivory, focused on the eastern United States generally since the 1800s and the development of instrumental records (1895). Climate largely has not warmed during 1981–2020 compared to 1895–1980, but precipitation has increased. Increased precipitation and land use (encompassing fire exclusion and forestation, with coarse fuel accumulation due to increased tree densities) have interacted synergistically to dampen wildfire frequency in the humid eastern U.S. For overall tree growth, increased precipitation, carbon fertilization, and land use (i.e., young, fast-growing dense stands) likely have been positive, generating a synergistic interaction. Human activities created conditions for expanding native tree species distributions, non-native species invasions, and damaging native species outbreaks. No strong evidence appears to exist for recent climate change or land use influences on deer populations and associated herbivory levels. In the future, a warmer and effectively drier climate may reverse synergistic and neutral interactions with land use, although effects of climate interactions with land use will vary by species. Management can help correct non-climate stressors due to land use and support resilient structures and species against climate change.