ntroduction: We previously showed that the addition of valproic acid (VPA), a histone deacetylase inhibitor, to fresh frozen plasma (FFP) resuscitation attenuates brain lesion size and swelling following traumatic brain injury (TBI) and hemorrhagic shock (HS). The goal of this study was to use computational biology tools to investigate the effects of FFPþVPA on the brain transcriptome following TBIþHS. Methods: Swine underwent TBIþHS, kept in shock for 2 h, and resuscitated with FFP or FFP þ VPA (n ¼ 5/group). After 6 h of observation, brain RNA was isolated and gene expression was analyzed using a microarray. iPathwayGuide, Gene Ontology (GO), Gene-Set Enrichment Analysis, and Enrichment Mapping were used to identify significantly impacted genes and transcriptomic networks. Results: Eight hundred differentially expressed (DE) genes were identified out of a total of 9,118 genes. Upregulated genes were involved in promotion of cell division, proliferation, and survival, while downregulated genes were involved in autophagy, cell motility, neurodegenerative diseases, tumor suppression, and cell cycle arrest. Seven hundred ninety-one GO terms were significantly enriched. A few major transcription factors, such as TP53, NFKB3, and NEUROD1, were responsible for modulating hundreds of other DE genes. Network analysis revealed attenuation of interconnected genes involved in inflammation and tumor suppression, and an upregulation of those involved in cell proliferation and differentiation. Conclusion: Overall, these results suggest that VPA treatment creates an environment that favors production of new neurons, removal of damaged cells, and attenuation of inflammation, which could explain its previously observed neuroprotective effects.