The Prairie Pothole Region (PPR) in central North America consists of millions of depressional wetlands that each have considerable potential to emit methane (CH₄). Changes in temperature and hydrology in the PPR from climate change may affect methane fluxes from these wetlands. To assess the potential effects of changes in climate on methane emissions, we examined the relationships between flux rates and temperature or water depth using six years of bi-weekly flux measurements during the snow-free period from six temporarily ponded and six permanently ponded wetlands in North Dakota, USA. Methane flux rates were among the highest reported for freshwater wetlands, and had considerable spatial and temporal variation. Methane flux rates increased with increasing temperature and water depth, and were especially high when conditions were warmer and wetter than average (163 ± 28 mg CH₄ m⁻² h⁻¹) compared to warmer and drier (37 ± 7 mg CH₄ m⁻² h⁻¹). Methane emission rates from permanent wetlands were less sensitive to changes in temperature and water depth compared to temporary wetlands, likely due to higher sulfate concentrations in permanent wetlands. While the predicted increase in temperature with climate change will likely increase methane emission rates from PPR wetlands, drier conditions could moderate these increases.