Microarray analysis was used to delineate gene expression patterns and profile changes following traumatic brain injury (TBI) in mice. A parallel microarray analysis was carried out in mice with TBI that were subsequently treated with minocycline, a drug proposed as a neuroprotectant in other neurological disorders. The aim of this comparison was to identify pathways that may be involved in secondary injury processes following TBI and potential specific pathways that could be targeted with second generation therapeutics for the treatment of neurotrauma patients. Gene expression profiles were measured with the compugen long oligo chip and real-time PCR was used to validate microarray findings. A pilot study of effect of minocycline on gene expression following TBI was also carried out. Gene ontology comparison analysis of sham TBI and minocycline treated brains revealed biological pathways with more genes differentially expressed than predicted by chance. Among 495 gene ontology categories, the significantly different gene ontology groups included chemokines, genes involved in cell surface receptor-linked signal transduction and pro-inflammatory cytokines. Expression levels of some key genes were validated by real-time quantitative PCR. This study confirms that multiple regulatory pathways are affected following brain injury and demonstrates for the first time that specific genes and molecular networks are affected by minocycline following brain injury.