Neuroinflammation has been recognized as a factor in the pathogenesis of neurodegenerative diseases. Esculentoside A (EsA), a saponin isolated from Phytolacca esculenta, has been reported to have anti-inflammatory activity. However, little research has been reported on the anti-neuroinflammatory effects of EsA. EsA concentration-dependently suppressed LPS-induced TNF-α, IL-1β, and PGE2 production. LPS-induced NF-κB activation was inhibited by treatment of EsA. Furthermore, EsA concentration-dependently up-regulated the expression of PPAR-γ. In addition, GW9662, a specific PPAR-γ inhibitor, reversed the anti-inflammatory effects of EsA. In conclusion, these results indicate that EsA exerts anti-inflammatory effects by activating PPAR-γ.