Background: The present study was designed to observe if different decompression profiles, calculated as a function of tissue supersaturation during ascent, would result in significantly different outcomes, measured through different physiological stress indicators, even in the absence of symptoms of decompression sickness. Aim: The aim of this study was to evaluate if simulated decompression profiles would affect the immune system, oxidative stress indicators, and heart rate variability. Methods: A total of 23 volunteers participated in two different experimental protocols in a dry hyperbaric chamber. These simulated dives comprised two different compression–decompression arrangements with the same maximum pressure and duration but different decompression profiles. Results: The shallow decompression profile with shorter deeper stops and longer shallow stops presented an increase in the standard deviation of the normal-to-normal R-R interval (a wide indicator of overall variability); the deep decompression profile with longer deeper stops and shorter shallow stops did not exhibit such increase. The shallow decompression profile resulted in an increase in neutrophil count and its microparticles (MPs), but no changes were observed for platelet count and its MPs, as well as for endothelial-derived MPs. In contrast, the deep decompression profile resulted in no changes in neutrophil count and its MPs, but a decrease in platelet count along with an increase in MPs from both platelets and endothelial cells. The observed difference might be related to different levels of decompression-related activation of immune system responses and oxidative processes triggered by different levels of inert gas supersaturation upon surfacing. Conclusion: From previous results and literature data, we present a tentative schematic of how the velocity of ascent would trigger (or not) pro-inflammatory and immune system responses that could ultimately lead to the development of decompression sickness. Relevance for patients: Increasing safety in exposure to hyperbaric environments and subsequent decompression by evaluating individual physiological responses to the process.