Water footprint is an important method to evaluate the degree of water exploitation and water pollution caused by human activities. The water footprint of production can be categorized into green water footprint, blue water footprint, and grey water footprint according to water resources. Green water footprint and blue water footprint evaluate water use and consumption, and grey water footprint assesses water pollution. The comprehensive analysis of green, blue, and grey water footprint of crop production guides water use management in agriculture. In this paper, we assessed the spatio-temporal patterns and influencing factors of the water footprint of main grain crops production in the Sanjiang Plain in China, and identified the pressure on regional water resources generated by grain crops production. The results showed that: (1) total water footprint of grain crops production in the Sanjiang Plain increased significantly from 2005 to 2018. The average proportions of green water footprint, blue water footprint, and grey water footprint in total water footprint were 28%, 8%, and 64%, respectively. (2) The water footprint of grain crops production was significantly different among cities or counties. At the city level, the water footprint of grain crops production in Jiamusi was the highest, accounting for 47% of the total amount of the Sanjiang Plain. At the county/district level, Fujin, Ilan, and Huanan were hotspot areas, together accounting for 32% of the total amount of the Sanjiang Plain. (3) Only considering blue water exploitation, grain crops production caused mild water stress on water resources in the Sanjiang Plain, while considering both blue and grey water footprint, grain crops production caused severe stress on regional water resources. Moreover, water stress levels varied among cities, in which Jiamusi producing nearly half of the grain yield in this region suffered the highest water stress while Hegang suffered the lightest water stress. (4) Rainfall, irrigation water use efficiency, fertilizer usage, cropping structure, and crop productivity affected the water footprint of crop production. Blue water footprint was the most sensitive to cropping structural changes, grey water footprint was the most sensitive to fertilizer usage changes, while total water footprint was the most sensitive to the change of crop productivity. If the following measures are adopted: the productivity of the crops increased by 10%, the chemical fertilizer use decreased by 10%, 10% of paddy fields turned to dryland crops, and the irrigation water use efficiency increased by 10%, the total water footprint can be reduced by 9.1%, 6.7%, 2.5%, and 0.1%, respectively. Considering both mitigation potential and feasibility, we suggest that reducing the amount of chemical fertilizer use, improving crop productivity, and optimizing the cropping structure should be considered for the sustainable management of regional water resources.