Wetlands are one of the most critical resources in Inner Mongolia Plateau. However, the region has experienced severe wetland loss in the context of global change. To quantify the dynamic change and the related driving forces, we extracted wetland information using multi-temporal Landsat images between 1993 and 2013 using ArcGIS platform and man-machine interactive interpretation. Dynamically changing characteristics for the past 20 years were analyzed, including wetland types and spatial distribution patterns of the wetlands in Inner Mongolia. We also performed correlation analysis and generalized linear models to quantify the contribution of natural and human factors to the changes in natural wetland area. Our results indicated that the total area of wetlands was 42421.2 km2 in 1993, and decreased to 38912.4 km2 in 2013, a decline ratio of 8.3%. Meanwhile, all types of wetlands showed a trend of transformation into non-wetlands. Anthropogenic factors led to the loss of natural wetlands in Inner Mongolia. In grasslands, mining coal was the dominant driver for natural wetland loss, while in arable lands, agricultural encroachment and irrigation were the primary driving forces. These findings can provide meaningful information for improving sustainable wetlands management strategies according to local conditions in different sub-regions.