The aim of current study is to investigate the effect of systemic administration of lipopolysaccharide (LPS) on the temporal pattern of cortical nuclear factor kappa B (NF-κB) binding activity, inflammatory response and secondary damage in the injured brain following traumatic brain injury (TBI). Right parietal cortical contusion in rats was made by using weight-dropping method. The rats were randomly divided into sham, LPS, TBI and TBI–LPS groups, with LPS injected intraperitoneally. NF-κB binding activity, cytokines, intercellular adhesion molecule-1 (ICAM-1) and brain damage were detected by electrophoretic mobility shift assay (EMSA), enzyme-linked immunosorbent assay (ELISA), immunohistochemistry and terminal deoxynucleotidyl-transferase-mediated biotin-dUTP nick end labeling (TUNEL) apoptosis, respectively. The results showed that systemic administration of LPS following TBI could induce an immediate, strong and persistent upregulation of NF-κB, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and ICAM-1 in the area surrounding the injured brain. As compared with rats of sham, LPS and TBI groups, NF-κB binding activity, TNF-α and IL-6 were significantly upregulated in the surrounding cortex of injured site as early as 3 h postinjury when challenged with LPS, kept at high level up to 7-days postinjury. ICAM-1-positive vessels and apoptotic TUNEL-positive cells in the injured brain were also significantly increased in TBI–LPS rats. It was concluded that inflammatory response and secondary brain damage occurred in the injured brain could be highly exacerbated by endotoxemia.