Oxidative stress (OS) is considered a pathogenic mechanism that, if not strictly controlled, triggers the onset and progression of many chronic and degenerative diseases. This investigation aimed to explore the potential attenuation of OS and cell apoptosis induced by benzo[a]pyrene (B[a]P) in albino rats using wild Silybum marianum seed ethanolic extract (SMSE). Thirty-six adult male albino rats were divided into six equal groups. Group (1) served as the normal control and received an intraperitoneal vehicle of single-dose corn oil (10 ml/kg/b. wt.). The remaining groups (2-6) were subjected to a single dose of B[a]P (125 mg/kg/b. wt.) dissolved in corn oil. Subsequently, group (2) was assigned as the positive control, while the other groups (3 to 6) received SMSE at doses of 200, 400, 600, and 800 mg/kg/d, respectively, by oral gavage for four weeks. B[a]P administration resulted in severe OS as evidenced by a significant (p≤0.05) increase in plasma oxidants levels (thiobarbituric acid reactive substances TBARS, No2, and No2/No3); and a marked drop in the levels of erythrocyte enzymatic antioxidants (glutathione peroxidase GSH-Px, catalase CAT, and superoxide dismutase SOD), non-enzymatic antioxidants (reduced glutathione GSH and oxidized glutathione GSSG) and plasma antioxidant vitamins (A, C, and E). Additionally, B[a]P exposure activated liver apoptosis by upregulating caspase-3 (a cell apoptosis executor) and Bax (a pro-apoptotic protein); and downregulating Bcl-2 (an anti-apoptosis marker). Treatment with SMSE markedly attenuated OS by suppressing plasma oxidants or restoring enzymatic and non-enzymatic antioxidant armories in a concentration-dependent manner. Moreover, the apoptotic proteins caspase-3 and Bax were inhibited, whereas the anti-apoptotic mediator Bcl-2 was activated. In conclusion, the obtained data provide potent proof of SMSE's efficiency as a preventative and curative natural remedy against B[a]P-induced oxidative stress damages.