<p>AbstractAim: Valproic acid (VPA) is a commonly used antiepileptic drug and known to have a neurotoxic effect, but its mechanism is not yetunderstood. In the present study, we aimed to determine how the VPA causes cell death in the brain and to evaluate the protectiveeffects of thymoquinone (TQ) on VPA-induced brain damage.Materials and Methods: Male Sprague–Dawley albino rats were divided into three groups: control, VPA (500 mg/kg/day) and VPA +TQ (500 mg/kg/day + 50 mg/kg/day) with seven rats in. At the end of the experiment, rats were sacrificed and brain samples weretaken to measure the expression levels of Receptor-interacting serine/threonine-protein kinase-1 (RIPK1) and -3 (RIPK3) genes byquantitative real-time PCR (qRT-PCR), NADPH oxidase-4 (NOX4) and, caspase-3 (CAS-3) expression by immunohistochemistry andthe structural changes in the brain tissue by histologically.Results: RIPK1 gene expression levels were significantly increased in the VPA group compared to the controls (p&lt;0.05) and adecrease in VPA + TQ group against the VPA group. Also, NOX-4 and CAS-3 production were increased in the VPA group comparedto the control group (p&lt;0.05), and there is a markedly decrease in the VPA + TQ group compared to the VPA group.Conclusion: VPA induced RIPK1-dependent apoptosis, leading to cell deaths in the brain and TQ reduced its effects. Therefore, TQuptake can be a supportive treatment method for long-term and high-dose VPA users to eliminate undesirable effects.Keywords: Apoptosis; RIPK1; thymoquinone; valproic acid<br></p>