Inner Mongolia is an important ecological zone of northern China and 67% of its land area is grassland. This ecologically fragile region has experienced significant vegetation degradation during the last decades. Although the spatial extents and rates of vegetation change have previously been characterized through various remote sensing and GIS studies, the underlying driving factors of vegetation changes are still not well understood. In this study, we first used time-series MODIS NDVI data from 2000 to 2016 to characterize the temporal trend of vegetation changes. These vegetation change trends were compared with climate and socioeconomic variables to determine the potential drivers. We used a set of statistical methods, including multiple linear regression (MLR), spatial correlation analysis, and partial least squares (PLS) regression analyzes, to quantify the spatial distribution of the driving forces and their relative importance to vegetation changes. Results show that the main driving factors and their impact magnitude (weight) are in the order of human activities (r = -0.785, p 0.05 VIP = 0.59). The area affected by human activities was 10.57%. Specific human activities, such as coal mining and grazing were negatively associated with vegetation cover, while eco-engineering projects had positive impacts. This study provided thorough quantification of driving forces of vegetation change and enhanced our understanding of their interactions. Our integrated geospatial-statistical approach is particularly important for sustainable development of ecosystem balance in Chen Barag Banner and other areas facing similar challenges.