Soil organic carbon (SOC) stocks of Prairie Pothole Region (PPR) wetlands in the central plains of Canada and the United States are highly variable due to natural variation in biota, soils, climate, hydrology, and topography. Land-use history (cropland, grassland) and land-management practices (drainage, restoration) also affect SOC stocks. We conducted a region-wide assessment of wetland SOC stocks using data from the Canadian and US portions of the PPR under various management types. Natural wetlands with no disturbance history in the wetland basin or surrounding catchment had considerably greater average SOC stocks in the upper (0–15 cm) soil profile than wetlands surrounded by cropland. Hydrologically restored wetlands did not show significantly greater SOC stocks than drained wetlands, but wetlands surrounded by restored grasslands did have greater SOC stocks in the upper soil profile than those surrounded by croplands. Similarities among cropped and restored wetlands likely were due to insufficient time since restoration, as well as high variability attributable to several environmental factors within the region. We conclude that avoided loss of natural wetlands from drainage and avoided loss of native grasslands from cropping have the most benefit for preserving wetland SOC stocks. Robust PPR SOC models that incorporate multiple abiotic, biotic, and land-use factors are required to determine where and when restoration is most effective for SOC sequestration.