Background: Phillyrin (Phi) is the main polyphenolic compound found in Forsythia suspensa. Recent studies have revealed that Phi has potent antioxidative and anti-inflammatory effects. However, whether Phi could relieve blood-brain barrier (BBB) damage following traumatic brain injury (TBI) remains unknown. Materials and Methods: Lipopolysaccharide (LPS) was used to activate primary microglia, which were then treated with different doses of Phi or the peroxisome proliferator-activated receptor-gamma (PPAR gamma) antagonist (GW9662). CCK-8 assay was used for evaluating cell viability, and the cytokines (including IL-1 beta, IL-6, TNF alpha, IL-4, IL-10, and TGF beta), microglial phenotypic markers (iNOS, COX2, and CD86 for "M1" polarization; Arg1, Ym1, and CD206 for "M2" polarization), PPAR gamma, and NF-kappa B were determined by RT-PCR, Western blot, or cellular immunofluorescence. Primary cultured mouse brain microvascular endothelial cells (BMECs) were stimulated by the condition medium (CM) from microglia. The cell viability, angiogenesis, and tight junction of BMECs were determined via CCK-8 assay, tube formation assay, and Western blot (for detecting MMP3, MMP9, ZO1, claudin-5, and occludin). Furthermore, the mouse TBI model was constructed and treated with Phi and/or GW9662. The BBB integrity was evaluated by H&E staining, Evans blue staining, and tissue immunofluorescence. Results: Phi markedly restrained the pro-inflammatory ("M1" state) cytokines and promoted anti-inflammatory ("M2" polarization) cytokines in LPS-mediated microglia. Phi mitigated "M1" polarization and promoted "M2" polarization of microglia via enhancing PPAR gamma and inhibiting the NF-kappa B pathway. The PPAR gamma antagonist GW9662 significantly repressed Phi-mediated anti-inflammatory effects. Meanwhile, Phi enhanced the viability, tube formation ability, and cell junction of BMECs. In the TBI mouse model, Phi promoted "M2" polarization, whereas it repressed the "M1" polarization of microglia. In addition, Phi reduced TBI-mediated BBB damage. However, the protective effects of Phi were reversed mainly by GW9662 treatment. Conclusion: Phi prevents BBB damage via inhibiting the neuroinflammation of microglia through the PPAR gamma/NF-kappa B pathway, which provides a potential therapeutic drug against TBI.