Water resources variability and availability in a basin affect river flows and sustain river ecosystems. Climate change and human activities disrupt runoff sequences, causing water environmental issues like river channel interruptions. Therefore, determining ecological flow in changing environments is challenging in hydrological research. Based on an analysis of long-term changes in hydrological and meteorological variables and interruption conditions in the semi-arid Liu River Basin (LRB), this study summarizes the controlling factors of river interruption at different temporal and spatial scales and proposes a framework to determine ecological flow under changing environments. Hydrological model and the monthly optimal probability distribution were used to determine the optimal ecological runoff of LRB. The results showed that from 1956 to 2017, precipitation and potential evapotranspiration in the basin showed no significant decreasing trend, but the streamflow significantly decreased, and the downstream interruption worsened, with an average annual interruption duration of 194days at Xinmin Station from 1988 to 2017. The controlling factors of river interruption are as follows: (1) soil and water conservation measures in the upstream significantly reduce the runoff capacity; (2) the operation mode of the controlling reservoir in the middle reaches changes from "all-year discharge" to "winter storage and spring release" to "combined storage and supply," severing the hydraulic connection between upstream and downstream; and (3) siltation in the downstream river channel coupled with over-extraction of groundwater increases the seepage capacity of the river. The monthly ecological flow of Naodehai Reservoir was determined by considering the monthly seepage losses after reconstructing the natural runoff using the SWAT model and determining the optimal probability distribution function for monthly runoff. The findings are important for downstream LRB ecological restoration and for determining the ecological flow of other river basins in changing environments.