Traumatic brain injury (TBI) is a common and serious clinical problem with high variability in injury severity. Current clinical therapies generally only manage downstream effects of TBI. Thus, there is an increasing interest in finding treatments that can directly address underlying physiological responses such as edema, cell apoptosis, and tissue oxidation. We applied open-source, clinician-accessible informatics methods that identified differentially expressed genes (DEGs) in curated TBI rodent models, found associated hub genes and genetic pathways, and determined novel chemical leads for treatments that target key pathways associated with secondary inflammatory injury in TBI. Differential expression analysis was performed by identifying DEGs between models of TBI and controls. Pathway analysis was completed to determine the up and down regulated genes enriched in each gene pathway and to delineate DEGs in post TBI models over a 48-h recovery period. A molecular similarity search using over 22,000 known molecules was then run against the identified ligands. The pathways determined to be relevant to secondary TBI were inflammation, oxidative stress, cell apoptosis, and angiogenesis, a marker for blood-brain barrier permeability. The similarity search yielded 95 potential ligand matches found in PubChem’s database. 20 ligands were determined to have potential in neuropathological treatment research or were associated with gene pathways relevant to TBI. The methodology reported in this study can be applied to other gene expression datasets to enable clinicians to identify viable treatment leads in rare or neglected diseases.