Oceans have been changing at the fastest pace since the beginning of the Holocene. The South Eastern Pacific (SEP), including the Humboldt Upwelling Ecosystem (HUE) is subject to changes in upwelling winds, temperature, El Niño, and the ever-increasing local anthropogenic stressors, all of which have been documented for surface coastal waters where in-situ and remote observations are readily available. Temporal and spatial changes in the adjacent deeper waters where diverse Mesophotic Ecosystems are found have been scarcely documented. These marine ecosystems have been the focus of ecological studies for less than two decades. Here we provide an overview of the thermal variability at mesophotic depths and assess their potential as climatic refugia along all SEP ecoregions. We analyzed a time series of temperature and salinity from a 19 yr reanalysis based on remote and in-situ observations (CTD, ARGO, XBTs, moorings) to quantify variability in the Tropical (0–5°S), Northern Warm Temperate (5–30°S); Southern Warm Temperate (30–39.5°S) and Magellanic subregions (39.5–45°S), at two mesophotic depth strata (50 and 100 m), and a reference surface (5 m) depth. We assessed variability in the seasonal, interannual (El Niño) and ‘long-term’ (ca. 20 yr) scales, and the relationship with wind velocities. The thermal depth gradient between surface and mesophotic depths did not change smoothly with latitude but peaked within the northern portion of the warm temperate subregion, decreasing towards lower and higher latitudes. Seasonal variation in temperature was also largest in the north and south temperate subregions and minimal in the Magellanic subregion. Depth dampening of seasonal temperature variation was also strengthened at intermediate latitudes and much reduced in the tropics, where seasonal variation at mesophotic depths was similar to that at the surface. The strong interannual El Niño events were identified at all depths in tropical and temperate subregions, with stronger standardized effects at mesophotic layers than at the surface. Long-term (ca. two decades) temperature trends were significant and changed direction from warming to cooling along the SEP but were generally patchier at mesophotic layers. Spatial temperature gradients have remained relatively stable over the past two decades and were stronger at the surface than at mesophotic depths, and stronger within the tropics than in all other subregions. Surprisingly, the velocity of climate change was patchier and generally faster at mesophotic layers than at the surface. We conclude that, judging solely by physical environmental conditions, mesophotic ecosystems may be used by species with very different temperature affinities in temperate subregions, while in the tropics, more overlap in temperature affinities of component species may be found. Importantly, while the seasonal amplitude is reduced at mesophotic depth in most subregions, except the tropics, interannual disturbances affect mesophotic depths at least as strongly as they do surface waters and climate change velocities are faster at mesophotic depths than at surface. Thus, these ecosystems are not sheltered from inter-annual and longer-term forcing and their biotas might be more vulnerable to climate change than shallow coastal ecosystems.