It is of great significance to systematically analyze the characteristics of the regional grain supply and demand balance, reveal the influence mechanism of crop sustainable development, and put forward effective countermeasures to achieve the goal of food security. This paper aims at addressing the unique geographical characteristics of Northwest China and the current lack of research on its food security. This paper systematically analyzes the temporal and spatial variation characteristics of the regional grain production, consumption and food security level. The main factors affecting regional food security are examined, and we put forward effective suggestions to promote regional sustainable production. The results show that the average annual growth rate of grain production in Northwest China from 2000 to 2021 was 3.4%, and the years of increased grain production accounted for 77.3%. The main reason for the increase in grain production was the increase in yield per unit area (average annual growth of 2.8%), of which the rice yield was the largest, up to 7.3 t/ha. Maize and wheat accounted for 60.7% and 23.4% of the total grain production in the region, respectively. From the perspective of the regional structure, Inner Mongolia contributed the most to the grain production in the region, accounting for 33.5% of the total output. Xinjiang, Shanxi, Shaanxi, Gansu, Ningxia and Qinghai contributed 17.1%, 15.4%, 15.2%, 13.0%, 4.5% and 1.3%, respectively, to grain production. From the perspective of the dietary structure, the grain consumption pattern in Northwest China has gradually changed from raw grains to animal products, which has undoubtedly increased the regional demand for grain. At present, since the increase in output is greater than the demand for food, the food self-sufficiency rate in the region has increased from 0.81 to 1.28. Since the grain yield per unit area in Xinjiang and Ningxia has a relative advantage over other provinces, to achieve regional food security for a long time, moderately increasing the grain planting area in these two provinces will help to promote regional food security. In addition, as the grains produced in the region are mainly wheat and corn, the yield level of wheat and corn in Xinjiang and Qinghai has a comparative advantage within Northwest China. Therefore, moderately increasing the planting area of wheat and corn in Xinjiang and Qinghai is of great significance in ensuring regional food security. The research results can provide theoretical support for the realization of regional food security and provide a reference for other regions in the world, to better serve global food security.