Abstract: Objective: To investigate the role and mechanism of mitochondrial oxidative stress in lead (Pb)-induced microglial inflammation. Methods: BV2 microglia cells were divided into 4 groups and treated with 0 μmol/L (control group), 1 μmol/L, 5 μmol/L and 10 μmol/L lead acetate, respectively. The mRNA expression levels of interleukin (IL)-6, IL-8 and tumor necrosis factor (TNF-α) in microglia were detected by reverse transcription-quantitative PCR (RT-qPCR). The activation state of microglia and the expression of mitochondrial reactive oxygen species (mtROS) were observed by immunofluorescence, and the mitochondrial membrane potential was detected by JC-1. C57BL/6 mice were divided into control group, Pb exposure group (Pb group) (100 ppm), MitoTEMPO treatment group (MitoTEMPO group) (5 mg/kg), MitoTEMPO combined with Pb treatment group (MitoTEMPO+Pb group), and the levels of serum and cerebral cortex inflammatory factors IL-1β and TNF-α were determined by enzyme-linked immunosorbent assay (ELISA). The levels of NLRP3, Caspase-1 and IL-1β in the hippocampus of mice were determined by western blotting. Results: Pb could activate BV2 microglia cells. Compared with the control group, the levels of IL-6, IL-8 and TNF-α mRNA in the Pb group were increased in a dosedependent manner, mtROS was increased, and mitochondrial membrane potential was decreased. MitoTEMPO could inhibit the activation of microglia in hippocampus of mice, decrease the levels of IL-1β and TNF-α in serum and cerebral cortex, and increase the levels of NLRP3, Caspase-1 and IL-1β proteins in hippocampus (all P＜0.05). Conclusion: Pb induces mitochondrial oxidative stress, which can activate microglia. The mechanism may be related to NLRP3 inflammasome activation.