Under the combined influences of climate changes and human activities, the hydrological regimes of the Wei River show remarkable variations which have caused many issues in the Wei River in recent decades such as a lack of freshwater, water pollution, flood disaster, and channel sedimentation. Hence hydrologic regime changes and potential human-induced impacts have been drawing increasing attention from local government and hydrologists. This study investigates hydrological regime changes in the natural and measured runoff series of four hydrologic stations on the main Wei River and quantifies features of their long-term change by analysing their historical annual and seasonal runoff data using several approaches: continuous wavelet transform, cross-wavelet, wavelet coherence, trend-free pre-whitening Mann-Kendall test, and detrended fluctuation analysis. By contrasting two different analysis results between natural and measured river runoff series, the impacts of human activities on the long-term hydrological regime in terms of spatio-temporal distribution in dominant periods, the trends and long-range memory of river runoff were investigated. The results show the following: (1) Periodic properties of the streamflow changes are the result of climate changes and precipitation changes in particular. Human activities play a minor role in the changes in periodic properties. (2) A significant decreasing trend can be observed in the natural streamflow series along the entire main stream of the Wei River, which should be attributed to human-induced influences in recent decades. (3) Decreasing streamflow in the Wei River may trigger serious shortages of freshwater, and the sustainable utilization of water resources in the Wei River basin may face a challenging situation. This study has important implications for the scientific management of water resources and enhancement of human mitigation of climate changes and human-induced water shortage in the Wei River basin.