The El Niño-Southern Oscillation (ENSO), originating in the central and eastern equatorial Pacific, is a defining mode of interannual climate variability with profound impact on global climate and ecosystems. However, an understanding of how the ENSO might have evolved over geological timescales is still lacking, despite a well-accepted recognition that such an understanding has direct implications for constraining human-induced future ENSO changes. Here, using climate simulations, we show that ENSO has been a leading mode of tropical sea surface temperature (SST) variability in the past 250 My but with substantial variations in amplitude across geological periods. We show this result by performing and analyzing a series of coupled time-slice climate simulations forced by paleogeography, atmospheric CO2 concentrations, and solar radiation for the past 250 My, in 10-My intervals. The variations in ENSO amplitude across geological periods are little related to mean equatorial zonal SST gradient or global mean surface temperature of the respective periods but are primarily determined by interperiod difference in the background thermocline depth, according to a linear stability analysis. In addition, variations in atmospheric noise serve as an independent contributing factor to ENSO variations across intergeological periods. The two factors together explain about 76% of the interperiod variations in ENSO amplitude over the past 250 My. Our findings support the importance of changing ocean vertical thermal structure and atmospheric noise in influencing projected future ENSO change and its uncertainty.