Abstract: Improving the economic efficiency of water use for crop production in China′s major grain-producing areas (MGPA) is greatly significant to promote national food security, water safety, rural revitalization, the Yangtze River protection, as well as the ecological protection and high-quality development of the Yellow River Basin. Regional economic efficiency of generalized water use for crop production (EEGWUC) was represented by the ratio of regional crops output value to the total amount of blue and green water consumption in the crop production. Considering both the five major staple crops like rice and wheat, and 12 non-staple crops such as sugarcane, peanut, cotton, etc., the spatio-temporal evolution characteristics of the EEGWUC was analyzed in the 13 provinces of MGPA in China during 2000-2018. With the improvement and supplement of the influencing factors in existing researches, this study analyzed the influencing factors of EEGWUC in MGPA based on the panel data regression method. The results show that: (1) from 2000 to 2018, annual mean of EEGWUC in any of the 13 provinces in China′s MGPA were in fluctuating upward trend, and the annual average of EEGWUC in MGPA increased from 140 CNY/ million tons to 267 CNY/ million tons. This efficiency in Jilin showed the most obvious fluctuation, while that in Hubei embodied the weakest fluctuation. The inter-provincial difference of EEGWUC in MGPA decreased with fluctuation, and the 13 provinces can be ranked by the EEGWUC annual average from the highest to the lowest as follows: Jiangsu (265 CNY/ million tons), Hunan, Jiangxi; Liaoning; Henan, Sichuan; Jilin, Hubei; Hebei, Anhui, Inner Mongolia, Heilongjiang and Shandong (144 CNY/million tons). (2) The significantly positive factors of EEGWUC in MGPA included fertilizer application per unit sown area, water use in the irrigation per unit area, the ratio of sown area of food crop to the regional sown area, the ratio of effective irrigation area to regional cultivating area, water-saving irrigation index, reservoir capacity per unit sown area, utilization coefficient of irrigation water. Meanwhile, amount of agricultural plastic film used per unit sown area, proportion of fixed asset investment in the GDP of the primary industry, provincial water use structure and educational level of the rural population, impacted the EEGWUC significantly and negatively. Based on this, suggestions were put forward to improve the EEGWUC in China′s MGPA, such as adjusting the mode of agricultural production, strengthening the construction and operation of water conservancy infrastructure, increasing agricultural subsidies and preferential policies for agriculture, allocate water resources scientifically and strengthening education and publicity, and improving the management of government financial expenditure.