<p>The mammalian brain uses several energy substrates during development, such as lactate, ketone bodies, and glucose, to avoid energy imbalances that may lead to cellular dysfunction. Sex differences in brain function are well-documented, with males being more susceptible to neurodevelopmental disturbances than females; however, the underlying reason for this vulnerability is not fully elucidated. Present study aimed to investigate sex differences in energy metabolism at different postnatal ages. Wistar rats of both sexes were evaluated on postnatal days (PND) 1, 7, 14, 21, and 60. Biochemical parameters included the immunocontent of ketone bodies (KB) and glucose transporters, glucose uptake in the hippocampus, and the levels of lactate, glucose, and beta-hydroxybutyrate (BOHB) in serum and cerebrospinal fluid. Moreover, beta-hydroxybutyrate dehydrogenase (BHD) activity was evaluated in the liver and the hippocampus. Immunofluorescence staining was performed to label the distribution of monocarboxylate transporters (MCTs) in the hippocampus and the corpus callosum. Serum lactate and BOHB levels were higher at PND1 than at other ages. Animals at PND14 predominantly utilize BOHB as a substrate, followed by a transition phase to glucose during weaning. Female rats exhibited an increase in the immunocontent of MCT2, MCT1, MCT4, and GLUT1 throughout postnatal development, suggesting a metabolic advantage over males due to greater uptake efficiency of energy substrates. Present findings reveal sex-specific differences in the expression of glucose and MCTs monocarboxylate transporters during postnatal brain development. A deeper understanding of these metabolic differences among healthy individuals may elucidate crucial sex-specific features of in neurological disorders, such as hypoxia–ischemia. This understanding could facilitate the advancement of more precise and targeted therapeutic interventions.</p>