Land degradation poses significant threats to the sustainability of ecosystem structures, functions, and services, leading to increasing ecological risks. However, integrative assessment of the ecological risk driven by land degradation remains a challenge. In this study, we established a methodological framework for assessing regional ecological risk by integrating degenerative land use transitions with multiple ecological indicators. Specifically, 11 degradation modes of land use transitions and 7 indicators on ecosystem structures, functions, and services are quantitatively integrated using remote sensing data from 2000 to 2020 in the Qinghai-Tibet Plateau of China. Results revealed that the comprehensive ecological risk of the plateau is higher in the southern and northern regions. Furthermore, we found that land development from forests towards cropland and degradation towards grasslands lead to higher ecological risks than grassland development and degradation. The ecological risk tends to show a significant distance decay pattern around the patches with land degradation. Our research framework provides an efficient, explicit, and transferable means of exploring spatiotemporal changes in ecological risk caused by degenerative land use transitions at the regional scale. It presents a constructive tool for facilitating regional-scale land use and ecosystem management planning and assessment.