Rationale <p>Oxiracetam (ORC) has been demonstrated to improve neurological function resulting from traumatic brain injury (TBI).</p> Objectives <p>This study aims to explore the precise molecular mechanism of ORC in the treatment of TBI.</p> Methods <p>TBI rat model was established and treated with ORC. Modified Garcia score, rotarod test and HE staining were employed to evaluate the neuroprotective effects of ORC. Subsequently, RNA-seq was conducted on the hippocampus of sham, TBI and ORC rats to identify differential expression (DE) lncRNAs and mRNAs. Functional analysis of DE lncRNAs and mRNAs was performed. The real-time quantitative polymerase chain reaction (qRT-PCR) was used to determine the expression of DE lncRNAs and DE mRNAs. Western blot was performed to explore important pathway in ceRNA networks.</p> Results <p>ORC has been demonstrated to effectively improve neurological function in TBI rats. A total of 10 ORC-treated DE lncRNAs and 61 DE mRNAs were obtained. A co-expression network comprising 79 lncRNA-mRNA pairs associated with the treatment of ORC was constructed. Furthermore, an lncRNA-miRNA-mRNA regulated ceRNA network was constructed, comprising 15 mRNAs, 41 miRNAs and 10 lncRNAs. Functional enrichment, qRT-PCR, and Western blot analysis showed that ORC improve neurological function of TBI rats by regulating multiple signaling pathways, including the JAK-STAT/PI3K-Akt pathway, as well as affecting the expression of key genes Prlr, Cdkn1a, and Cldn1.</p> Conclusion <p>Our study reveals the mechanism of ORC therapy in TBI rats, which mainly relies on the regulation of the JAK-STAT/PI3K-Akt pathway and the influence on the expression of key genes Prlr, Cdkn1a, and Cldn1.</p>