Luteolin (LUT) is a glycosylated flavonoid compound that has multiple beneficial pharmacological and biological impacts. The current investigation was undertaken to evaluate the putative neuroprotective potency of LUT against neuronal damage induced by lead acetate (PbAc). Twenty-eight rats were placed into four equal groups. Group 1: served as the control group, group 2: rats were supplemented orally with LUT (50 mg kg⁻¹), group 3: rats were intraperitoneally injected with PbAc (20 mg kg⁻¹), and group 4: rats were pretreated with LUT before PbAc injection with the same doses. All animals were treated for 7 days. The exposure to PbAc increased the concentration of lead in the cortical tissue, neuronal lipid peroxidation, and nitric oxide (NO) production and decreased the antioxidant enzymes. Additionally, PbAc enhanced a neuroinflammatory response in the cortical tissue through increasing the pro-inflammatory cytokines secretion and inducible NO synthase expression. Moreover, cortical cell death was recorded following PbAc intoxication as evidenced by the enhancement of the proapoptotic and inhibiting the antiapoptotic markers. Interestingly, LUT supplementation reversed the cortical adverse reactions induced by PbAc. Taken together, these findings may suggest that LUT may be useful for attenuating neuronal damage induced by PbAc through inhibiting the oxidative damage, neuroinflammation, and the cortical cell death.