Exploring the coupling characteristics of regional water resources and food security helps to promote the sustainable development of grain production and is of great significance for achieving global food security. From the aspects of regional “water supply”, “water use” and “water demand”, the coupling characteristics of water resources and food security were systematically revealed; the new challenges faced by regional food security from the perspective of water resources were clarified; and effective ways to promote the utilization of regional water resources and the sustainable development of grain production were explored. This paper took Northwest China, which is the most arid region, where water-resource utilization and food security are in contradiction, as the research area. The water-resource load index, the water footprint of grain production and the water-consumption footprint were used to quantify the regional water-resource pressure index, as well as the residential grain-consumption types, population urbanization, the industrial-grain-processing industry and their corresponding water-consumption footprints from 2000 to 2020. The coupling characteristics of water resources and food security were systematically revealed. The results showed the following: (1) In 2000–2020, the water-resource load index increased from 4.0 to 10.7, and the load level increased from III to I. At the same time, agricultural water resources were largely allocated elsewhere. (2) During the period, the food rations showed a significant decreasing trend, and the average annual reduction was 3.4% (p < 0.01). The water footprint of animal products increased, particularly for beef and poultry (the average annual growth rates were 9.9% and 6.3%, respectively). In addition, the water footprint of industrial food consumption increased by 297.1%. (3) With the improvement of the urbanization level, the water-consumption footprint increased by 85.9%. It is expected that the water footprint of grain consumption will increase by 39.4% and 52.3% by 2030 and 2040, respectively. Exploring how to take effective measures to reduce the water footprint to meet food-security needs is imperative. This study proposed measures to improve the utilization efficiency of blue and green water and reduce gray water and the grain-consumption water footprint from the aspects of regional planting-structure optimization potential, water-saving irrigation technology, dietary-structure transformation and virtual water trade; these measures could better relieve the water-resource pressure and promote the sustainable development of grain production and water-resource utilization.