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Several recent studies have highlighted differences in simulated properties of El Niño–Southern Oscillation (ENSO) under transient and equilibrium responses to increasing CO2. However, the reasons behind these disparate responses and the extent to which they are robust to different scales of CO2 forcing remain unclear. In this study, we adopt a climate system model with reduced SST bias in the eastern tropical Pacific and incrementally apply abrupt increases in CO2, analyzing outputs after each simulation reaches quasi-equilibrium with the imposed forcing. The results suggest that ENSO activity under quasi-equilibrium first increases and then decreases with increasing CO2, peaking in simulations with CO2 concentrations similar to the present day. Bjerknes–Jin stability analysis indicates that changes in the ENSO growth rate result primarily from changes in the thermocline feedback and thermodynamic damping terms. While thermodynamic damping increases monotonically with increasing CO2, the positive thermocline feedback varies within the range of internal variability up to twice the preindustrial value of CO2 and then weakens sharply with further increases. The mechanisms behind these changes include weaker mean ocean upwelling and weaker dynamical coupling between the atmosphere and subsurface ocean associated with substantial near-surface freshening at higher levels of CO2. These changes steepen the thermodynamic barrier to mixing between the surface and subsurface, weakening the east–west temperature gradient in the mean state and suppressing variability in the cold tongue. Analysis of similar model simulations from the Coupled Model Intercomparison Project (CMIP6) archive indicates that changes in the Bjerknes–Jin stability index are robust but do not establish a consensus as to the mechanisms behind them. Significance Statement: This study investigates how El Niño–Southern Oscillation changes with increasing CO2 forcing by using a global model with improved tropical Pacific climate. The simulations roughly correspond to scenarios in which emissions are reduced to maintain CO2 concentrations at near-constant values over a long period, with levels ranging from about 2/3 to more than 5 times the present-day concentration. Analysis of these simulations suggests that ENSO activity is strongest when CO2 concentrations are similar to the present-day and becomes substantially weaker when CO2 is more than double its present-day value. Reduced ENSO activity with further increases in CO2 is caused by weaker interactions between the atmosphere and the subsurface ocean. Both the amplitude of warm (El Niño) events and the occurrence frequency of warm and cold (La Niña) events decrease as ENSO events become first more difficult to grow and then more difficult to trigger with increasing CO2. [ABSTRACT FROM AUTHOR]