Background: Tartrazine (Tz) is one of the most commonly used food additive and synthetic color that is added to food for attracting the consumers' vision. However, it might cause many toxic effects on the long run. Objectives: This study aimed to evaluate the potential ameliorating effect of thymoquinone (TQ) against possible neurotoxic effect of Tz. Materials and Methods: Forty adult male rats were allocated into four groups: Group (1) received distilled water, Group (2) was given 10 mg TQ /kg b.wt., Group (3) was given Tz (7.5 mg/kg b.wt.) and Group (4) was given TQ concurrently with Tz. All treatments were given orally daily for 30 days. Brain neurotransmitters; norepinephrin (NE), dopamine (DA), serotonin (5HT) and gamma amino butyric acid (GABA) beside glutathione (GSH), catalase (CAT), malondialdehyde (MDA), tumor necrosis factor-α (TNF- α), Bcl-2 associated X (Bax) protein, and B-cell lymphoma-2 (Bcl-2) were evaluated in cerebellar homogenate. Also, histological and immunohistochemical examinations for cerebellar tissue were studied. Results: Tartrazine significantly decreased NE, DA, 5HT and GABA; as well as GSH and CAT with increased MDA, while TNF-α and Bax showed significant increase versus decreased Bcl-2. Nevertheless, TQ significantly increased NE, DA, 5HT and GABA as well as GSH and CAT beside Bcl-2, while decreasing MDA, TNF-α and Bax. Histologically, the swelling and vacuolar degeneration of the cerebellar cortex with decrease numbers of Purkinje cells and the increased apoptotic cell number that were noticed in Tz treated group improved after TQ supplementation. Conclusion: Thymoquinone could be a good candidate for modulation of Tz – induced neurotoxicity through its antioxidant, neurotransmitter modifying, anti-neuroinflammatory and anti-apoptotic effects.