The heterogeneity of traumatic brain injury (TBI)-induced secondary injury has greatly hampered the development of effective treatments for TBI patients. Targeting common processes across species may be an innovative strategy to combat debilitating TBI. In the present study, a cross-species transcriptome comparison was performed for the first time to determine the fundamental processes of secondary brain injury in Sprague-Dawley rat and C57/BL6 mouse models of TBI, caused by acute controlled cortical impact. The RNA sequencing data from the mouse model of TBI were downloaded from the Gene Expression Omnibus (ID: GSE79441) at the National Center for Biotechnology Information. For the rat data, peri-injury cerebral cortex samples were collected for transcriptomic analysis 24 hours after TBI. Differentially expressed gene-based functional analysis revealed that common features between the two species were mainly involved in the regulation and activation of the innate immune response, including complement cascades as well as Toll-like and nucleotide oligomerization domain-like receptor pathways. These findings were further corroborated by gene set enrichment analysis. Moreover, transcription factor analysis revealed that the families of signal transducers and activators of transcription (STAT), basic leucine zipper (BZIP), Rel homology domain (RHD), and interferon regulatory factor (IRF) transcription factors play vital regulatory roles in the pathophysiological processes of TBI, and are also largely associated with inflammation. These findings suggest that targeting the common innate immune response might be a promising therapeutic approach for TBI. The animal experimental procedures were approved by the Beijing Neurosurgical Institute Animal Care and Use Committee (approval No. 201802001) on June 6, 2018.