The El Niño-Southern Oscillation (ENSO) is one of the most important components of the global climate system, but its potential response to an anthropogenic increase in atmospheric CO2 remains largely unknown. One of the major limitations in ENSO prediction is our poor understanding of the relationship between ENSO variability and long-term changes in Tropical Pacific oceanography. Here we investigate this relationship using palaeorecords derived from the geochemistry of planktonic foraminifera. Our results indicate a strong negative correlation between ENSO variability and zonal gradient of sea-surface temperatures across the Tropical Pacific during the last 22 ky. This strong correlation implies a mechanistic link that tightly couples zonal sea-surface temperature gradient and ENSO variability during large climate changes and provides a unique insight into potential ENSO evolution in the future by suggesting enhanced ENSO variability under a global warming scenario.