As an endogenous compound essential for energy homeostasis, creatine holds a fundamental role in the bioenergetics of the brain, an organ with high metabolic requirements. This review provides a synthesis of current knowledge on the impact of creatine on the functions of the central nervous system (CNS). The brain, which is capable of de novo creatine synthesis, demonstrates an increase in its internal concentrations following supplementation; however, this effect is less significant than in muscle tissue and is constrained by the blood-brain barrier, among other factors. The development of effective CNS-targeted dosing strategies remains a subject of ongoing research. An overview of the literature suggests that creatine supplementation may beneficially influence cognitive performance, particularly under conditions of elevated metabolic demand like stress or sleep deprivation, with the potential to enhance memory and mitigate fatigue. Nonetheless, findings from the cited research are inconsistent due to methodological heterogeneity and a common failure to directly measure brain creatine levels. Reports on creatine’s antidepressant properties are particularly encouraging, with preclinical and initial clinical studies pointing to its potential utility (e.g., via the mTORC1 pathway) in augmenting mood disorder treatments. Moreover, the authors examine the use of creatine in chronic fatigue syndrome, where evidence supports improvements in physical performance and reductions in pain intensity, although its effect on generalized fatigue remains ambiguous.