Wetlands in the mid- and high-latitudes are particularly vulnerable to environmental changes and have declined dramatically in recent decades. Climate change and human activities are arguably the most important factors driving wetland distribution changes which will have important implications for wetland ecological functions and services. We analyzed the importance of driving variables for wetland distribution and investigated the relative importance of climatic factors and human activity factors in driving historical wetland distribution changes. We predicted wetland distribution changes under climate change and human activities over the 21st century using the Random Forest model in a mid- and high-latitude region of Northeast China. Climate change scenarios included three Representative Concentration Pathways (RCPs) based on five general circulation models (GCMs) downloaded from the Coupled Model Intercomparison Project, Phase 5 (CMIP5). The three scenarios (RCP 2.6, RCP 4.5, and RCP 8.5) predicted radiative forcing to peak at 2.6, 4.5, and 8.5 W/m² by the 2100s, respectively. Our results showed that the variables with high importance scores were agricultural population proportion, warmness index, distance to water body, coldness index, and annual mean precipitation; climatic variables were given higher importance scores than human activity variables on average. Average predicted wetland area among three emission scenarios were 340,000 ha, 123,000 ha, and 113,000 ha for the 2040s, 2070s, and 2100s, respectively. Average change percent in predicted wetland area among three periods was greatest under the RCP 8.5 emission scenario followed by RCP 4.5 and RCP 2.6 emission scenarios, which were 78%, 64%, and 55%, respectively. Losses in predicted wetland distribution were generally around agricultural lands and expanded continually from the north to the whole region over time, while the gains were mostly associated with grasslands and water in the most southern region. In conclusion, climatic factors had larger effects than human activity factors on historical wetland distribution changes and wetland distributions were predicted to decline remarkably over time under climate change scenarios. Our findings have important implications for wetland resource management and restoration because predictions of future wetland changes are needed for wetlands management planning.