Abstract Studying the response of a climate system to perturbations has practical significance. Standard methods in computing the trajectory-wise deviation caused by perturbations may suffer from the chaotic nature that makes the model error dominate the true response after a short lead time. Statistical response, which computes the return described by the statistics, provides a systematic way of reaching robust outcomes with an appropriate quantification of the uncertainty and extreme events. In this paper, information theory is applied to compute the statistical response and find the most sensitive perturbation direction of different El Niño–Southern Oscillation (ENSO) events to initial value and model parameter perturbations. Depending on the initial phase and the time horizon, different state variables contribute to the most sensitive perturbation direction. While initial perturbations in sea surface temperature (SST) and thermocline depth usually lead to the most significant response of SST at short and long ranges, respectively, initial adjustment of the zonal advection can be crucial to trigger strong statistical responses at medium range around 5–7 months, especially at the transient phases between El Niño and La Niña. It is also shown that the response in the variance triggered by external random forcing perturbations, such as the wind bursts, often dominates the mean response, making the resulting most sensitive direction very different from the trajectory-wise methods. Finally, despite the strong non-Gaussian climatology distributions, using Gaussian approximations in the information theory is efficient and accurate for computing the statistical response, allowing the method to be applied to sophisticated operational systems. Significance Statement The purpose of this work is to better understand how El Niño–Southern Oscillation (ENSO) responds to changes in its initial state and internal dynamics or external forcings. A statistical quantification of this response allows for the comprehension of the triggering conditions and the effect of climate change on the occurrence frequency and strength of each type of ENSO event. Such a study also allows to detect the most sensitive perturbation directions, which has practical significance in guiding anthropogenic activities. The approach used to study the response in this work is through the framework of information theory, which allows for an unbiased and robust assessment of the statistical response that is not affected by the turbulent dynamics of the system.