The Shijiahe Culture (ca. 4800–4100 yr BP), which originated in the middle Yangtze Basin, was a milestone of prehistoric Chinese civilization. To reveal the interactions between climatic changes and human activities during this time interval, the geochronology and multiple proxies (pollen and heavy metals) of samples from a 220-cm-deep outer wall at the Sanfangwan Site (a typical site of the Shijiahe Culture) were analyzed. Radiocarbon dating indicates that the age range of the Sanfangwan Site is ca. 4800 to 4100 cal. yr BP. From ca. 4800 to 4600 cal. yr BP (the early Shijiahe Culture), pollen assemblages were dominated by Gramineae and an anthropogenic plant community (e.g. Ranunculaceae, Chenopodiaceae, Labiatae, and Cruciferae), indicating an expansion in rice agriculture during this interval. High metal concentrations in the same interval indicate a large flux of metals from smelting and farming activities. Between ca. 4600 and 4100 cal. yr BP (the middle and late Shijiahe Culture), decreases in Gramineae and anthropogenic pollen mirrored the recession of farming. Concurrent decreases in heavy metals may be attributable to a decline in the smelting industry. Three episodes of high pollen concentrations and visible increases in hygrophyte pollen, Pinus pollen, and fern spores at 4600–4550, 4450–4350, and 4200–4100 cal. yr BP probably indicate the occurrence of several flooding events during the middle and late Shijiahe Culture, resulting in the migration of local inhabitants. This study highlights the driving effect of flood events on the collapse of the Shijiahe Culture.