The phenotypic manifestation of lead toxicity includes cognitive, learning, and memory decline which is associated with neuronal injuries and death and been a major challenge in public health especially in developing countries. Thus, we explore the prophylactic potentials of luteolin in prefrontal Pb intoxication. Thirty-six (36) male Wistar Rats were used for this research and di-vided into six (6) groups of six animals each and were treated orally as follows: Group 1-Normal saline (0.5ml daily for 14 days); Group 2- PbCl3 (50mg/kg of PbCl3 daily for 14 days); Group 3- luteolin (100mg/kg of LUT daily for 14 days); Group 4- luteolin and PbCl3 (50mg/kg PbCl3 and 100mg/kg LUT daily for 14 days); Group 5- PbCl3 then luteolin (50mg/kg of PbCl3 daily for 14 days followed by 100mg/kg of LUT daily for 14 days); Group 6- luteolin then PbCl3 (100mg/kg of LUT daily for 14days followed by 50mg/kg of PbCl3 daily for 14 days). We measured cerebral oxidative redox parameters, G6PDH, IL-6, acetylcholinesterase levels, and total protein profiles using ELISA and biochemical assay kits. We also examined cerebral morphology and the Nissl profile with H&E and toluidine blue staining techniques, as well as astrocytic morphology and synaptic integrity with anti-GFAP and anti-synaptophysin antibodies. As a result of Pb perturba-tion, luteolin treatment inhibits MDA, IL-6, and AChE expression while increasing antioxidant enzyme activities (SOD, GPx) and G6PDH. Furthermore, luteolin has significant prophylactic po-tential against Pb-induced neuronal injuries and modulates astrocyte actions, preserving synap-tic integrity and thus improving cognition, learning, and memory. Taken together, our findings indicate that luteolin may be a promising candidate for managing and treating Pb neural intoxi-cation.