Natural methane (CH
4
) emissions from aquatic ecosystems may rise because of human-induced climate warming, although the magnitude of increase is highly uncertain. Using an exceptionally large CH
4
flux dataset (~19,000 chamber measurements) and remotely sensed information, we modeled plot- and landscape-scale wetland CH
4
emissions from the Prairie Pothole Region (PPR), North Americaâs largest wetland complex. Plot-scale CH
4
emissions were driven by hydrology, temperature, vegetation, and wetland size. Historically, landscape-scale PPR wetland CH
4
emissions were largely dependent on total wetland extent. However, regardless of future wetland extent, PPR CH
4
emissions are predicted to increase by two- or threefold by 2100 under moderate or severe warming scenarios, respectively. Our findings suggest that international efforts to decrease atmospheric CH
4
concentrations should jointly account for anthropogenic and natural emissions to maintain climate mitigation targets to the end of the century.