Significant inroads have been achieved in our understanding of neuropathology with the discovery of the crosstalk between the nervous and immune systems. In the neuro-immune crosstalk, interleukin-15 (IL-15) and its receptors are essential mediators. The IL-15 system has been found to act on peripheral metabolism, including glucose, lipid and energy homeostasis. Nevertheless, whether it promotes neuropsychiatric disorders by affecting CNS metabolism remains unclear, warranting further exploration. Herein, we performed untargeted GC-MS metabolomics between Il-15rα mutant mice and wildtype mice. The results showed that Il-15rα mutation led to metabolic alternations in the cortex and hippocampus, some of which potentially exert detrimental effects on brain health. The identification of neurotransmitter (GABA and 5-hydroxytryptophan), energy (glycolysis and ketone bodies) and lipid (cholesterol and fatty acids) metabolism disorders corroborates the findings of previous studies on the IL-15 system. Moreover, anandamide and glyoxylate and dicarboxylate were novel potential candidates. These findings enhance our understanding of the IL-15 system and its interactions with neuropsychiatric disorders.