BACKGROUND: Excessively activated M1 microglia release proinflammatory factors that can cause neuronal death and contribute to the development of Parkinson's disease (PD). Recent research indicates that spermidine, a naturally occurring polyamine, may have anti-inflammatory properties. Nonetheless, the specific role of spermidine in Parkinson's disease, particularly how it affects microglia-driven neuroinflammation and the balance between M1 and M2 polarization, is still not fully understood. METHODS: We examined the effects of spermidine on the polarization of M1/M2 microglia in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD and lipopolysaccharide (LPS)-stimulated BV2 cells. Methods like RT-PCR, western blotting, and immunofluorescence were used to examine how spermidine influences the polarization of microglia. RESULTS: In vivo, spermidine pretreatment reduced the activation of M1 microglia and encouraged the transformation of microglia into the M2 phenotype in the substantia nigra (SN) of PD mice. Additionally, spermidine decreased the release of inflammatory factors and lessened the death of dopaminergic neurons in the SN of these mice. In vitro, spermidine indirectly protected neurons from death by affecting microglial polarization. Furthermore, spermidine preconditioning led to decreased phosphorylation of NF-κB, STAT1, and p38 MAPK, while enhancing the phosphorylation of STAT6, both in vivo and in vitro. Additionally, we observed that the supernatant from BV2 cells was cultured with SH-SY5Y neurons. The findings revealed that the supernatant from LPS-activated BV2 cells notably reduced the viability of SH-SY5Y cells, as well as the levels of brain-derived neurotrophic factor (BDNF), TrkB, PI3K, and p-AKT. However, these effects were significantly reversed by pretreatment with spermidine. CONCLUSION: Our research found that spermidine reduced M1 microglial polarization, partially through the inhibition of the NF-κB, STAT1, and p38 MAPK pathways, and encouraged M2 microglial polarization by activating the STAT6 pathway. This action helped to mitigate neuroinflammation in both the MPTP mouse model of Parkinson's disease and LPS-stimulated BV2 cells. Additionally, spermidine provided indirect neuroprotection by activating BDNF-TrkB-PI3K/AKT signaling pathways.