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Studying the Indian Summer Monsoon (ISM) evolution and its relationship with human civilization is of great scientific significance, as it can provide insights into the evolution of monsoon system as well as the interaction between ISM-driven climate changes and societal development. However, the historical evolution of the ISM and its influence on civilization on a centennial scale remains unclear. Here, we employed high-resolution (~19 yr) multi-indicator analysis (grain size, magnetic susceptibility, and loss on ignition) of Qionghai Lake core sediments to reconstruct the Holocene evolution history of the ISM climate and explore its potential driving mechanism, and further examine the influence of ISM variations on the development of human civilization. The results indicate three stages of ISM climate variations during the past 13.6 cal ka BP: strengthening ISM and increasingly humid climate before 8 cal ka BP; strong ISM and significantly humid climate between 8.0 and 3.0 cal ka BP, corresponding to the Holocene Climatic Optimum (HCO); weakening ISM and dry climate after 3.0 cal ka BP. Furthermore, our results indicate that the Holocene ISM climate was regulated by sub-orbital cycles, with a dominant ~2000-year (yr) quasi-periodic oscillation, linked to solar activity, the Atlantic Meridional Overturning Circulation (AMOC) and sea-surface temperature (SST) variations, and a significant ~500-yr quasi-periodic oscillation in the mid-Holocene, associated with fluctuations in the El Niño-Southern Oscillation (ENSO). ISM variations have influenced the development of prehistoric cultures since the mid-Holocene. From 6.0 to 3.0 cal ka BP, the strengthening of the ISM contributed to the prosperity of human cultures through increased precipitation, expanded agriculture, growing population and human activities. After 3.0 cal ka BP, despite a weakening of ISM, human activities became the dominant factor influencing the development of civilization.