To understand the characteristics of hydrological regime evolution and the main driving factors in the main stream of the Xijiang River under the changing environment, the runoff series was divided into natural and changing periods by identifying its abrupt point, and the change degrees of various hydrological indicators were quantitatively investigated using the range of variability approach based on indicators of hydrologic alteration. The degree of hydrological alteration and Dundee hydrological regime assessment method(DHRAM)were used to assess the overall change degree of hydrological regime, and the principal component analysis method was used to select the most ecologically relevant hydrological indicators and capture the key hydrological variables. Furthermore, the impacts of climate change and human activities on hydrological regime in the river basin were quantitatively assessed using the random forest model combined with residual analysis. The results show that 32 hydrological indicators at four hydrological stations are dominated by medium and low degrees of alteration. The degrees of hydrological alteration at Tian’e, Qianjiang, Wuxuan, and Wuzhou stations were 64.7%, 61.34%, 51.70%, and 51.89%, respectively. The hydrological regime change levels at the four stations were 3, 3, 2, and 3, respectively according to the results of DHRAM, and the overall hydrological regime change degree at the four stations was determined to be moderate. The change degrees of hydrological regime at Tian’e and Qianjiang stations on the middle and upper reaches are higher than that at Wuxuan and Wuzhou stations on the middle and lower reaches. Therefore, the ecological protection on the middle and upper reaches should be paid more attention. Both climate change and human activities are important driving factors for the hydrological regime evolution in the main stream of the Xijiang River.The contribution rates of climate change to the hydrological regime evolution at Tian’e, Qianjiang, Wuxuan, and Wuzhou stations were 25.65%, 60.07%, 50.29%, and 55.22%, respectively. The impact of climate change on the hydrological regime in the middle and lower reaches of the Xijiang River Basin is greater than that in the upper reaches.