The large and rapid climate change event that occurred around 4200 years ago (hereafter the 4.2-kyr event that marks the onset of the Meghalayan stage) is one of the most significant climatic anomalies in the Holocene. It may have exerted profound societal impact globally; however, its triggering mechanism remains uncertain. Here we present a high-resolution, well-dated pollen record covering this interval from the Tianluoshan archaeological site in East China. Our results show that the hydroclimatic conditions in the study area across this event strikingly resembled the regional expression of modern El Nifio-Southem Oscillation (ENSO) and exhibited in-terdecadal ENSO-like variability from ca. 4.50 to 4.00 cal kyr BP. Also, our pollen data indicate a marked shift toward an overall increased intensity and frequency of ENSO-like climate variability from ca. 4.50 to 4.30 cal kyr BP, which was immediately followed by a decline of rice-based agriculture, providing direct evidence for the causal link between climate deterioration and the collapse of Neolithic civilization in East China some 4200 years ago. This observation is in accord with the enhanced ENSO variability reconstructed from proxy records in the tropical Pacific Ocean. As ENSO is intimately coupled with the Asian summer monsoon and the Intertropical Convergent Zone (ITCZ), we suggest that the enhanced ENSO-like climate variability may have triggered the 4.2-kyr event.