Hypoxia has been recently proposed to drive microglia to produce proinflammatory cytokines, including interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) and IL-6. Considering the fact that propolis has hepatoprotective, antitumor, antioxidative and anti-inflammatory effects, it may have protective effects against the hypoxia-induced neuroinflammation. In the present study, propolis (50 μg/ml) was found to significantly inhibit the hypoxia-induced cytotoxicity and the release of proinflammatory cytokines. Furthermore, propolis significantly inhibited the hypoxia-induced generation of reactive oxygen species (ROS) and the activation of nuclear factor-κB (NF-κB) in microglia. Moreover, systemic treatment with propolis (8.33mg/kg, 2 times/day, ip) for 7 days significantly suppressed the microglial expression of IL-1β, TNF-α, IL-6 and 8-oxo-deoxyguanosine in the somatosensory cortex of mice subjected to hypoxia (10% O₂, 4 h). These observations indicate that propolis suppresses the hypoxia-induced neuroinflammation through inhibition of the NF-kB activation in microglia. Therefore, propolis can be used as pharmacological intervention preventing cognitive deficits in aging and aging-related neurodegenerative diseases.