There is an urgent requirement to understand how large fluctuations in tropical heat distribution associated with the El Niño–Southern Oscillation (ENSO) will respond to anthropogenic emissions of greenhouse gases. Intervals of global warmth in Earth history provide a unique natural laboratory to explore the behavior of ENSO in a warmer world. To investigate interannual climatic variability, specifically ENSO, in the mid-Piacenzian Warm Period (mPWP) (3.26–3.03 Ma), we integrate observations from the stable isotopes of multiple individual planktonic foraminifera from three different species from the eastern equatorial Pacific with ENSO simulations from the Hadley Centre Coupled Model version 3 (HadCM3), a fully coupled ocean-atmosphere climate model. Our proxy data and model outputs show persistent interannual variability during the mPWP caused by a fluctuating thermocline, despite a deeper thermocline and reduced upwelling. We show that the likely cause of the deeper thermocline is due to warmer equatorial undercurrents rather than reduced physical upwelling. We conclude that the mPWP was characterized by ENSO-related variability around a mean state akin to a modern El Niño event. Furthermore, HadCM3 predicts that the warmer Pliocene world is characterized by a more periodic, regular-amplitude ENSO fluctuation, suggestive that the larger and deeper west Pacific warm pool is more easily destabilized eastward. These conclusions are comparable to the observed trend over the last 40 years to more regular and intense ENSO events. Future research must resolve whether global warming alone, or in concert with tectonic factors, was sufficient to alter ENSO variability during warm intervals of the Pliocene.