The agro-pastoral ecotone serves as an important ecological transition zone between grassland and cropland. It plays a crucial role in providing forage and maintaining the ecological security of Northern China. China has initiated many ecological restoration projects in the agro-pastoral ecotone. Separating the affecting factors of anthropogenic activities and natural factors change on grassland may help guide future ecological restoration projects. This study investigated the grassland change over the agro-pastoral ecotone in Inner Mongolia (APEI) using land use data, vegetation index, and monthly climate data, social and economic data from 2010 to 2020. Two indicators were introduced to evaluate the grassland change in quality and quantity. The average annual maximum NDVI of grassland within each sample was used as a proxy for grassland quality, and the proportion of grassland within each sample was used as a proxy for grassland quantity. The driving mechanisms of grassland quality were examined on different types of grassland. The results showed that (1) from 2010 to 2020, the quantity of grassland in APEI slightly decreased while the quality of the grassland significantly improved; (2) the change in grassland quality was jointly caused by natural factors and human activities, with 66.77% being attributed to natural factors and 33.23% to human activities. In some areas, the alteration in grassland quality was solely determined by either the impacts of natural factors or human-induced disturbances; and (3) temperature and precipitation played different roles in affecting grassland quality among different types of grassland. In some areas, anthropogenic activities, such as farmland and population, would affect grassland quality. The findings of this study would contribute to the understanding of the mechanism of ecological environmental changes in the agro-pastoral ecotone and guide the planning and implementation of future ecological restoration projects in agro-pastoral areas.