There is growing evidence that fine particulate matter (PM 2.5) is a considerable risk factor for neurodegenerative diseases. Scorpion venom heat-resistant synthetic peptide (SVHRSP) plays a neuroprotective effect by promoting neurogenesis and neuron axon growth. In this study, SVHRSP inhibited the level of TLR4, autophagy and PM2.5-induced microglia M1 polarization, thereby promoting Phosphorylation of PI3K and AKT, inhibiting the expression of NF-κB. Moreover, SVHRSP suppressed the cytotoxic factors and increased the cytoprotective factor. This research demonstrates that SVHRSP relieves PM 2.5 -induced microglial polarization via TLR4-mediated autophagy activating PI3K/AKT/NF-κB signaling pathway, which provides new insights for the treatment of PM 2.5 -induced neurodegenerative diseases. [Display omitted] • Scorpion venom heat-resistant synthetic peptide inhibits PM 2.5 -induced M1 polarization of microglia. • Scorpion venom heat-resistant synthetic peptide inhibits microglial autophagy induced by PM 2.5. • TLR4-mediated autophagy activating PI3K/AKT/NF-κB signaling pathway to attenuate microglial M1 polarization. • Scorpion venom heat-resistant synthetic peptide inhibits the release of cytotoxic factors from microglia. [ABSTRACT FROM AUTHOR]