Recently, we reported that quercetin (Que) could alleviate immunotoxicity induced by pristine multi-walled carbon nanotubes (MWCNTs) in mice. In the present study, we explored whether Que could also relieve MWCNTs-induced neurotoxicity. MWCNTs injection induced a dose-dependent neurotoxic effect in mice as evidenced by increased oxidative stress, inflammation, and pyroptosis in the brain. However, treatment with Que ameliorated MWCNTs-induced neurotoxicity as revealed by 1) elevated acetylcholinesterase (AChE) activity, 2) reduced lipid peroxidation biomarker malondialdehyde (MDA), 3) improved antioxidant status as indicated by increased levels of reduced glutathione (GSH) and activities of superoxide dismutase (SOD), catalase (CAT), as well as upregulated expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) genes, 4) decreased levels and expression of inflammatory biomarkers [nitric oxide (NO), interleukin 1 beta (IL1ß), tumor necrosis factor-alpha (TNF α), and nuclear factor kappa B (NF-κB)], 5) downregulated expression of pyroptosis-related genes [nod-like receptor protein inflammasome 3 (Nlrp3) and caspase 1 (Casp1)] but with no effect on the apoptotic Casp3 gene, 6) minimized axonal degeneration and number of microglia in the cerebral medulla, and 7) diminished the number of degenerated neurons in hippocampus and cerebellum. Taken together, Que could ameliorate MWCNT-induced neurotoxicity through antioxidant, anti-inflammatory, and anti- pyroptotic mechanisms.