The 4.2 ka event that occurred during the period from 4500–3900 a BP was characterized by cold and dry climates and resulted in the collapse of civilizations around the world. The cause of this climatic event, however, has been under debate. We collected four corals (Porites lutea) from Yongxing Island, Xisha Islands, South China Sea, dated them with the U-series method, and measured the annual coral growth rates using X-ray technology. The dating results showed that the coral growth ages were from 4500–3900 a BP, which coincide well with the period of the 4.2 ka event. We then reconstructed annual sea surface temperature anomaly (SSTA) variations based on the coral growth rates. The growth rate-based SSTA results showed that the interdecadal SSTA from 4500–3900 a BP was lower than that during mod times (1961–2008 AD). A spectral analysis showed that the SSTA variations from 4500–3900 a BP were under the influence of El Ni?o-South Oscillation (ENSO) activities. From 4500–4100 a BP, the climate exhibited La Ni?a-like conditions with weak ENSO intensity and relatively stable and lower SSTA amplitudes. From 4100–3900 a BP, the climate underwent a complicated period of ENSO variability and showed altating El Ni?o- or La Ni?a-like conditions at interdecadal time scales and large SSTA amplitudes. We speculate that during the early and middle stages of the 4.2 ka event, the cold climate caused by weak ENSO activities largely weakened social productivity. Then, during the end stages of the 4.2 ka event, the repeated fluctuations in the ENSO intensity caused frequent extreme weather events, resulting in the collapse of civilizations worldwide. Thus, the new evidence obtained from our coral records suggests that the 4.2 ka event as well as the related collapse of civilizations were very likely driven by ENSO variability.