Wetlands in the Prairie Pothole Region (PPR) are forecast to retract in their ranges due to climate change, and potholes that typically contain ponded water year-round, which support a larger proportion of biological communities, are most sensitive to climate change. In addition to climate, land use activities and topography also influence ponded water amounts in PPR wetlands. However, topography is not typically included in models forecasting the impacts of climate change on PPR wetlands. Using a combination of variables representing climate, land cover/land use and topography, we predicted wetland permanence class in the southern Boreal Forest, Parkland and Grassland natural regions of the Alberta PPR (N = 40 000 wetlands). We show that while climate and land cover/land use were strong predictors of wetland permanence class, topography was as important, especially in the southern Boreal Forest and Parkland natural regions. Our misclassification error rates for the gradient boosting models for each natural region were relatively high (43–60) though our learning rates were low (< 0.1) and our maximum tree depths shallow (5–7) to balance bias and overfitting. Clearly, factors in addition to climate, topography and land cover/land use influence wetland permanence class (i.e., basin size, depth, ground water connectivity, etc.). Despite classification errors, our results indicate that climate was the strongest predictor of wetland permanence class in the Parkland and Grassland natural regions, whereas topography was most important in the southern Boreal Forest Natural Region among the three domains we considered.