Inflammatory responses and oxidative stress damage the integrity of the blood-brain barrier (BBB), which is a primary pathological modulator of neurodegenerative diseases. Brain endothelial cells are crucial components of BBB. In the present study, the effect of oxyresveratrol on lipopolysaccharide (LPS)-induced brain endothelial (bEnd.3) cells was assessed. Our results showed that oxyresveratrol diminished protein expressions of inducible nitric oxide synthase (iNOS) and adhesion molecules including intercellular adhesion molecule (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), nitric oxide (NO) production, and proinflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor (TNF-α) in LPS-elicited bEnd.3 cells. These anti-inflammatory effects were mediated through suppressing nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways. In addition, we found that oxyresveratrol reduced reactive oxygen species (ROS) levels. To conclude, the current results demonstrated the protective role of oxyresveratrol against LPS-induced inflammation and oxidative stress in bEnd.3 cells, suggesting its potential effect for mitigating neurodegenerative and cerebrovascular diseases.