Lead (Pb) is a heavy metal with high toxicity that can cross the blood-brain barrier and accumulate in brain tissue, causing serious neurological disorders. The aim of this study is to evaluate the potential protective effect of chrysin (CHR) against Pb-induced neurotoxicity. Thirty-five male Sprague Dawley rats were divided into five groups: Control, CHR (50 mg/kg), Pb, Pb+CHR (25 mg/kg), and Pb+CHR (50 mg/kg). Rats were administered CHR (25 or 50 mg/kg) and Pb (30 mg/kg) orally for 7 days. Twenty-four hours after the last treatment, the rats were sacrificed under mild sevoflurane anesthesia by decapitation, and brain tissue samples were collected. Biochemical and histopathological methods were used to measure cholinergic enzyme activity, DNA damage, and oxidative stress parameters in brain tissue. CHR reduced levels of glial fibrillary acidic protein (GFAP), acetylcholinesterase (AChE), and 8-hydroxy-2'-deoxyguanosine (8-OHdG) caused by Pb. Due to its antioxidant properties, CHR decreased Pb-induced lipid peroxidation while increasing glutathione (GSH) levels and the activities of catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx). Based on biochemical and immunohistochemical analyses, CHR reduced cyclooxygenase-2 (COX-2), myeloperoxidase (MPO), nuclear factor kappa-B (NF-κB), neuronal nitric oxide synthase (nNOS), prostaglandin E2 (PGE-2), and p53 levels. These findings suggest that CHR may exert a therapeutic effect by alleviating oxidative stress and inflammation induced by Pb-induced neurotoxicity.