Improving the utilization efficiency of agricultural water resources (AWRUE) in major grain-producing areas (MGPA) is an effective means to ensure grain production. Using a DEA model and ESDA, this study explored the temporal and spatial characteristics of AWRUE in the main grain-producing areas of the middle reaches of the Yangtze River (MRYR) from 2006 to 2020 and analyzed the influencing factors via the Tobit model. The results indicate that (1) from 2006 to 2020, the comprehensive efficiency of AWRUE was 0.733, which was at a high level but not as effective as that of DEA; (2) AWRUE showed a characteristic of “high in the northwest and low in the southeast”; and (3) the added value of the primary industry positively impacted AWRUE. The effective irrigated area, per capita disposable income of rural residents, and per capita water resources had a negative impact on AWRUE. In the future, the following suggestions should be proposed to guide the effective utilization of regional water resources: improving water-saving technology, strengthening publicity and education, conducting regional cooperation and assigning water-saving strategies. Moreover, scientific references are provided for promoting AWRUE.