The El Niño Southern Oscillation (ENSO) is Earth’s dominant source of interannual climate variability, but its response to global warming remains highly uncertain1. To improve our understanding of ENSO’s sensitivity to external climate forcing, it is paramount to determine its past behaviour by using palaeoclimate data and model simulations. Palaeoclimate records show that ENSO has varied considerably since the Last Glacial Maximum (21,000 years ago)2, 3, 4, 5, 6, 7, 8, 9, and some data sets suggest a gradual intensification of ENSO over the past ~6,000 years2, 5, 7, 8. Previous attempts to simulate the transient evolution of ENSO have relied on simplified models10 or snapshot11, 12, 13 experiments. Here we analyse a series of transient Coupled General Circulation Model simulations forced by changes in greenhouse gasses, orbital forcing, the meltwater discharge and the ice-sheet history throughout the past 21,000 years. Consistent with most palaeo-ENSO reconstructions, our model simulates an orbitally induced strengthening of ENSO during the Holocene epoch, which is caused by increasing positive ocean–atmosphere feedbacks. During the early deglaciation, ENSO characteristics change drastically in response to meltwater discharges and the resulting changes in the Atlantic Meridional Overturning Circulation and equatorial annual cycle. Increasing deglacial atmospheric CO2 concentrations tend to weaken ENSO, whereas retreating glacial ice sheets intensify ENSO. The complex evolution of forcings and ENSO feedbacks and the uncertainties in the reconstruction further highlight the challenge and opportunity for constraining future ENSO responses.