In order to scientifically evaluate the water use efficiency (WUE) in the middle reaches of the Yangtze River, 13 evaluation indexes were selected from the five dimensions of comprehensive, industrial, agricultural, domestic and ecological water use to construct the WUE evaluation model based on MCW-grey TOPSIS. The weight of each index was calculated by the mixed cross-weighting (MCW) method of G1 method, entropy weight method and coefficient of variation method. TOPSIS method and grey relational degree analysis were combined to evaluate the WUE of the three provinces in the middle reaches of the Yangtze River from 2015 to 2019, and the spatio-temporal differences of WUE in the three regions were analyzed from the five dimensions mentioned above. Results show that the efficiency of regional WUE level in the middle reaches of Yangtze river presented a steady upward trend in time series; the WUE of Hunan Province and Hubei Province were higher during the evaluation period on space sequence, whereas that of Jiangxi province was lower; furthermore, the relative closeness of the three regions differentiated greatly in all the five dimensions. According to the analysis, the main problems of water use in the middle reaches of the Yangtze River are revealed, which can provide a theoretical basis for the research of regional water use efficiency and application of water saving measures.