The development of neuroprotective agents has important clinical significance. Bavachin is a flavonoid compound in Psoralea corylifolia, which has multiple biological activities, however its neuroprotective effect and molecular mechanism remain unclear. We found that bavachin inhibited neuroinflammation and also exerted significant antioxidative stress effects. Furthermore, we found that bavachin exerted neuronal protective and anti-apoptotic effects. Further studies showed that bavachin increased Bcl-2 expression, while inhibited Bax expression, and also inhibited the decrease of mitochondrial membrane potential. As for the mechanism, the results displayed that bavachin upregulated Sirt1 and Nrf2 expression in vitro and in vivo, and inhibited the phosphorylation level of p65 in vivo. Taken as a conclusion, this study first provided evidence that bavachin inhibited neuronal damage caused by neuroinflammation and oxidative stress through the activation of Sirt1/Nrf2 pathway and inhibition of NF-κB pathway, and bavachin might be a potential candidate for treating neurodegenerative diseases.