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This paper presents a novel framework comprising analytical, hydrological, and remote sensing techniques to separate the impacts of climate variation and regional human activities on streamflow changes in the Karkheh River basin (KRB) of western Iran. To investigate the type of streamflow changes, the recently developed DBEST algorithm was used to provide a better view of the underlying reasons. The Budyko method and the HBV model were used to investigate the decreasing streamflow, and DBEST detected a non-abrupt change in the streamflow trend, indicating the impacts of human activity in the region. Remote sensing analysis confirmed this finding by distinguishing land-use change in the region. The algorithm found an abrupt change in precipitation, reflecting the impacts of climate variation on streamflow. The final assessment showed that the observed streamflow reduction is associated with both climate variation and human influence. The combination of increased irrigated area (from 9 to 19% of the total basin area), reduction of forests (from 11 to 3%), and decreasing annual precipitation has substantially reduced the streamflow rate in the basin. The developed framework can be implemented in other regions to thoroughly investigate human vs. climate impacts on the hydrological cycle, particularly where data availability is a challenge. [ABSTRACT FROM AUTHOR]