Closed head injury (CHI) can lead to both neurological disabilities and systemic alterations through HPA axis activation. A dysregulated HPA function allows relocation of energy substrates and alterations in metabolic pathways and systemic inflammation. Assessment of time-dependent changes in serum metabolites and inflammatory markers showed unique pattern between mild and moderate injured rats. These alterations were found to be associated with HPA hyperactivity with increased serum corticosterone levels and hypothalamic microglial activation post mild and moderate TBI. The study suggests an important relation between HPA axis induced changes in systemic metabolomics.