Land-use change is a prominent feature of the Anthropocene. Transitions between natural and human-managed ecosystems affect biogeochemical cycles in many ways, but soil processes are among the least understood. We used a global meta-analysis (62 studies, 1670 paired comparisons) to examine effects of land conversion on soil–atmosphere fluxes of methane (CH4) and nitrous oxide (N2O) from upland soils, and determine soil and environmental factors driving these effects. Conversion from a natural ecosystem to any anthropogenic land use increased soil CH4 and N2O fluxes by 234 kg CO2-equivalents ha−1 y−1, on average. Reversion of managed ecosystems to that resembling natural ecosystems did not fully reverse those effects, even after 80 years. In general, neither the type of ecosystem converted, nor the type of subsequent anthropogenic land use, affected the magnitude of increase in soil emissions. Land-use changes in wetter ecosystems resulted in greater increases in CH4 fluxes, but reduced N2O fluxes. An interacting suite of soil variables influenced CH4 and N2O fluxes, with availability of inorganic nitrogen (that is, extractable ammonium and nitrate), pH, total carbon, and microclimate being strong mediators of effects of land-use change. In addition, time after a change in land use emerged as a critical factor explaining the effects of land-use change—with increased emissions of both greenhouse gases diminishing rapidly after conversion. Further research is needed to elucidate complex biotic and abiotic mechanisms that drive land-use change effects on soil greenhouse gas emissions, but particularly during this initial disturbance when emissions are greatest relative to native vegetation. Efforts to mitigate emissions will be severely hampered by this gap in knowledge.