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The Guanzhong Basin in central China features a booming economy and has suffered severe drought, resulting in serious groundwater depletion in the last 30 years. As a major water resource, groundwater plays a significant role in water supply. The combined impact of climate change and intensive human activities has caused a substantial decline in groundwater recharge and groundwater levels, as well as degradation of groundwater quality and associated changes in the ecosystems. Based on observational data, an integrated approach was used to assess the impact of climate change and human activities on the groundwater system and the base flow of the river basin. Methods included: river runoff records and a multivariate statistical analysis of data including historical groundwater levels and climate; hydro-chemical investigation and trend analysis of the historical hydro-chemical data; wavelet analysis of climate data; and the base flow index. The analyses indicate a clear warming trend and a decreasing trend in rainfall since the 1960s, in addition to increased human activities since the 1970s. The reduction of groundwater recharge in the past 30 years has led to a continuous depletion of groundwater levels, complex changes of the hydro-chemical environment, localized salinization, and a strong decline of the base flow to the river. It is expected that the results will contribute to a more comprehensive management plan for groundwater and the related eco-environment in the face of growing pressures from intensive human activities superimposed on climate change in this region.