Although a fragile climate region, the Taihu Lake Basin is among the most developed regions in China and is subjected to intense anthropogenic interference. In this basin, water resources encounter major challenges (e.g., floods, typhoons, and water pollution). In this study, the impacts of climate changes and human activities on hydrological processes were estimated to aid water resource management in developed regions in China. The Mann-Kendall test and cumulative anomaly curve were applied to detect the turning points in the runoff series. The year of 1982 divides the study period (1956~2008) into a baseline period (1956~1981) and a modified period (1982~2008). The double mass curve method and the hydrological sensitivity method based on the Budyko framework were applied to quantitatively attribute the runoff variation to climate changes and human activities. The results demonstrated that human activities are the dominant driving force of runoff variations in the basin, with a contribution of 83~89%; climate changes contributed to 11~17% of the variations. Moreover, the subregions of the basin indicated that humans severely disturbed the runoff variation, with contributions as high as 95~97%.