Background: To explore protective impact and underlying processes of tormentic acid (TA) against microglial-mediated neuroinflammation and oxygen-glucose deprivation/reoxygenation (OGD/R)-induced neuronal injury. Methods: HT22 neuronal cells and BV2 microglial cells underwent OGD/R to mimic ischemia-reperfusion injury in vitro. TA was administered at various concentrations before the OGD/R procedure. Cells viabilities were evaluated using cell counting kit-8 (CCK8) and Lactate Dehydrogenase (LDH) assays, while Western blotting and flow cytometry (FCM) were employed to assess apoptosis. Inflammatory cytokines were quantified by quantitative Polymerase Chain Reaction (qPCR) and Enzyme-Linked Immunosorbent Assay (ELISA). The involvement of the Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) axis was examined with Western blotting. Results: TA significantly enhanced cell viability in HT22 cells stimulated by OGD/R and reduced LDH release. TA markedly inhibited neuronal apoptosis induced by OGD/R. Furthermore, TA suppressed pro-inflammatory cytokines’ production for BV2 microglia after OGD/R exposure. Conditioned media from TA-treated microglia attenuated apoptosis in co-cultured HT22 neurons. Furthermore, TA inhibited NF-κB activation in both microglial and neuronal cells. Conclusions: Tormentic acid exerts neuroprotective effects regarding ischemia-reperfusion injury by reducing microglial-mediated neuroinflammation and suppressing NF-κB axis.