Inhalation of high concentrations of carbon dioxide (CO₂) at atmospheric pressure can be toxic with dose-dependent effects on the cardiorespiratory system or the central nervous system. Exposure to both hyperbaric and hypobaric environments can result in decompression sickness (DCS). The effects of CO₂ on DCS are not well documented with conflicting results. The objective was to review the literature to clarify the effects of CO₂ inhalation on DCS in the context of hypobaric or hyperbaric exposure. The systematic review included experimental animal and human studies in hyper- and hypobaric conditions evaluating the effects of CO₂ on bubble formation, denitrogenation or the occurrence of DCS. The search was based on MEDLINE and PubMed articles with no language or date restrictions and also included articles from the underwater and aviation medicine literature. Out of 43 articles, only 11 articles were retained and classified according to the criteria of hypo- or hyperbaric exposure, taking into account the duration of CO₂ inhalation in relation to exposure and distinguishing experimental work from studies conducted in humans. Before or during a stay in hypobaric conditions, exposure to high concentrations of CO₂ favors bubble formation and the occurrence of DCS. In hyperbaric conditions, high CO₂ concentrations increase the occurrence of DCS when exposure occurs during the bottom phase at maximum pressure, whereas beneficial effects are observed when exposure occurs during decompression. These opposite effects depending on the timing of exposure could be related to 1) the physical properties of CO₂, a highly diffusible gas that can influence bubble formation, 2) vasomotor effects (vasodilation), and 3) anti-inflammatory effects (kinase-nuclear factor and heme oxygenase-1 pathways). The use of O₂-CO₂ breathing mixtures on the surface after diving may be an avenue worth exploring to prevent DCS.