With fast development of economy and trade globalization, the water resources system has undergone profound changes due to the overconsumption of physical water and the complex virtual water flow. China is poor in water and rich in arable land for the north, but rich in water and poor in arable land for the south. The spatial mismatch of water and food production has posed a great threat to sustainable development. To quantify the virtual water flow with grain trade and evaluate its influence on the regional water resources system, this study simulated the interprovincial virtual water flow embedded in grain transportation based on a linear optimization model and assessed the water pressure induced by virtual water flow. Results show that the annual virtual water flow (as much as 73.46 billion m3 in 2012) associated with interprovincial grain trade is mainly from the North to the South. The grain output areas are mainly located in the Northeast, Northwest, and the North China Plain, while the grain input areas are mainly distributed in the eastern and southern coastal provinces with well-developed economies. According to the estimation, when China’s food demand reaches a peak of 650 million tons in 2030, the virtual water flow will further increase and the volume of virtual water flowing out of Northeast China will be up to 50 billion m3, accounting for 90% of the total virtual water flow. The increasing the virtual water outflow in North China will severely exceed the local water resources capacity in the arid and semi-arid areas and have an obvious negative impact on sustainable development in Northern China. Further improving the water use efficiency, adjusting the structure of spatial grain production distribution and physical-virtual water coupled management are effective countermeasures to ensure the coordination safety of food and water in China.