Lead (Pb) is a pervasive environmental neurotoxicant that causes neurodegeneration through oxidative stress, inflammation, mitochondrial dysfunction, and apoptosis. This study evaluated apoptotic, inflammatory and oxidative biomarkers in the brain striatum of mice exposed to Pb and treated with aqueous extract of Diospyros mespiliformis. Twenty-five male mice were divided into five groups. All groups, except the control (Group 1) received Pb (50 mg/kg) and were subsequently treated with D. mespiliformis extract (200 mg/kg b.wt (Group 3), 400 mg/kg (Group 4) or vitamin E (100 mg/kg, Group 5), while Group 2 mice received 50mg/kg b.wt of Pb only. At the end of 28 days exposure and treatment, brain striatum was obtained, homogenized and used for biochemical assays which includes Caspase -3, DNA fragmentation, Tumor necrosis factor – α, myeloperoxidase, total protein, reduced glutathione and protein thiol in the laboratory following standard operating methods. Results indicated that exposure to Pb causes significant decreased (p < 0.05) in levels of caspase – 3, nitric oxide and percentage DNA fragmentation and an elevation (p < 0.05) in levels of TNF – α, reduced glutathione, protein thiol and activity of myeloperoxidase. Treatment with aqueous extract of D. mesipiliformis elevated the levels of caspase – 3 and reduced the levels of protein thiol reduced glutathione and myeloperoxidase activity. Together, these findings suggest that D. mespiliformis exerts neuroprotective effects which is comparable to vitamin E a potent antioxidant through anti-oxidant, anti-inflammatory and anti-apoptotic effects. D. mesipiliformis may also have potential as a natural intervention for heavy metal–induced neurodegeneration.