Evaluating the spatiotemporal evolution of grain supply-demand balance and its influencing factors on the Qinghai-Tibet Plateau is crucial for ensuring food security and sustainable agricultural development. It plays a strategic role in strengthening border areas, promoting economic growth in ethnic minority regions, and ensuring social stability. This study utilizes a comprehensive approach, combining consumption statistics, production-sales balance index, spatial trend surface analysis, and the OPGD model, to investigate the spatiotemporal changes in the grain supply-demand balance on the Qinghai-Tibet Plateau from 1990 to 2020, as well as the underlying factors driving these changes. Additionally, the study aims to provide policy recommendations for enhancing food security and facilitating sustainable agricultural development in the Qinghai-Tibet Plateau. The research results reveal that the self-sufficiency rate of grain on the Qinghai-Tibet Plateau increased from 106.53% to 120.21% between 1990 and 2020. The regional grain supply-demand relationship shifted from a state of tight balance to balanced supply and demand overall. However, notable regional disparities exist in the grain supply-demand pattern. The intersection of grain shortages and severe shortages occurs in regions such as the northern Tibetan Plateau, Qinghai Plateau, Gannan Plateau, western part of the Qaidam Basin, and the Sichuan-Tibet alpine valley areas. Areas with grain surplus and abundance are concentrated in the Yarlung Zangbo River and its two tributaries in southern Tibet, the Hehuang Valle, the river valleys in the high mountain canyons of the Sichuan-Tibet region, and the oasis agricultural areas in the Pamir-Kunlun Mountains region. These areas are predominantly agricultural counties. The critical equilibrium zone is distributed in a belt-like pattern along the northern and southern border areas of the Qinghai-Tibet Plateau. The spatial variation in grain production on the Qinghai-Tibet Plateau is mainly influenced by regional disparities in natural conditions, differences in input factors, and economic development gaps. Furthermore, there is a synergistic strengthening effect between economic factors and input factors. Labor and capital have consistently been the two most critical production factors influencing grain production on the Qinghai-Tibet Plateau. The impact of fertilizer input intensity has decreased, while the influence of agricultural technology investment has significantly risen. The explanatory power of income level, food accessibility, food consumption structure, and population structure on the spatial differentiation of grain consumption on the Qinghai-Tibet Plateau weakened in sequence. Recommendations include improving the food security level of the Qinghai-Tibet Plateau through grain production and sales cooperation, agriculture and animal husbandry cooperation, adjustment of planting structures, enhancement of internal and external transportation infrastructure, and local grain reserves.