<p>Microglia-mediated neuroinflammation plays an important role in the pathogenesis of Parkinson’s disease (PD). Studies have shown that butylphthalide (3-n-butylphthalide or NBP) can play an anti-inflammatory role in other diseases by regulating the activation of microglia. This study investigates the neuroprotective and anti-inflammatory effects of NBP in a mouse model of Parkinson’s disease (PD) induced by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The primary aim was to determine whether NBP can improve symptoms of PD by modulating microglial activation and to explore the underlying mechanisms involved. Motor function (assessed via Open Field and Pole Climbing tests), dopaminergic neuronal loss, and activation of different microglial subtypes were assessed in control, MPTP-treated, and NBP + MPTP-treated mice. A p38 phosphorylation inhibitor + MPTP group was also established to investigate potential mechanisms of NBP action. Mice treated with NBP exhibited significantly improved motor function and reduced dopaminergic neuronal loss compared to MPTP-treated mice. In PD mice, pro-inflammatory factor expression was elevated, anti-inflammatory factor expression was reduced, and the expression of arginase-1 (arg-1), a marker for M2 microglia, was decreased. NBP treatment resulted in reduced levels of pro-inflammatory factors, increased levels of anti-inflammatory factors, and elevated arg-1 expression. Additionally, inhibition of p38 phosphorylation further decreased pro-inflammatory factor expression while increasing both anti-inflammatory factor levels and arg-1 expression. The findings indicate that NBP regulates neuroinflammation and improves symptoms of PD by promoting the transformation of microglia to the M2 phenotype, likely mediated through the p38 phosphorylation pathway.</p>