Microglia cells have been reported to mediate hypoxia-induced inflammation through the production of proinflammatory cytokines, including interleukin-1 beta (IL-1β), tumor necrosis factor alpha (TNF-α), and IL-6. Given the fact that the activation of the type 2 cannabinoid receptor (CB2R) provides antioxidative and anti-inflammatory results, it is suspected that its selective agonist, trans-caryophyllene (TC), may have protective effects against hypoxia-induced neuroinflammatory responses. In this study, TC was found to significantly inhibit hypoxia-induced cytotoxicity as well as the release of proinflammatory cytokines, including IL-1β, TNF-α, and IL-6, through activation of BV2 microglia following hypoxic exposure (1 % O2, 24 h). Furthermore, TC significantly inhibited hypoxia-induced generation of reactive oxygen species (ROS) in mitochondria as well as the activation of nuclear factor kappa B (NF-κB) in microglia. Importantly, TC's effects on inhibiting the activation of NF-κB and the secretion of inflammatory cytokines can be abolished by muting the CB2R using small RNA interference. These observations indicate that TC suppresses the hypoxia-induced neuroinflammatory response through inhibition of NF-κB activation in microglia. Therefore, TC may be beneficial in preventing hypoxia-induced neuroinflammation.