The transcription factor nuclear factor erythroid-2 related factor 2 (Nrf2) is a dominant manager to inhibit oxidative and inflammatory damage. Fenretinide (Fen) is a novel agent, showing significant role in regulating oxidative stress and inflammatory response. However, its effects on lipopolysaccharide (LPS)-induced brain injury are still unclear. In the present study, we explored the regulatory role of Fen in LPS-triggered neuroinflammation, and the underlying molecular mechanisms. Results here indicated that Fen treatment markedly improved Nrf2 expression and nuclear translocation in mouse brain endothelial cell line bEnd.3 cells, and promoted Nrf2-antioxidant responsive element (ARE) transcription activity, as well as its down-streaming signals, which was Nrf2-dependent. Fen also exhibited cytoprotective role in LPS-stimulated bEnd.3 cells through improving anti-oxidant capacity and inhibiting inflammation by the blockage of nuclear factor-kappa B (NF-κB) signaling. Mouse model with brain injury induced by LPS, Fen administration markedly attenuated the behavior impairments, blood-brain-barrier (BBB) and the histological changes in hippocampus samples. Additionally, Fen attenuated oxidative stress and blunted inflammation in hippocampus of LPS-challenged mice. Therefore, results in the study highlighted the protective role of Fen against LPS-elicited brain injury.