Sunset Yellow FCF (E110) is a water‐soluble synthetic dye that has adverse neurobehavioral effects. Coenzyme Q10 (CoQ10) is known as a neuroprotective agent. The present study aimed to evaluate the effects of post‐weaning exposure to Sunset Yellow FCF on behavioral and structural changes in the adult rat medial prefrontal cortex (mPFC) and the protective effects of CoQ10. The weanling rats were randomly divided into six groups: distilled water, CoQ10 (10 mg/kg/day), and low (2.5 mg/kg/day) and high (70 mg/kg/day) doses of Sunset Yellow FCF with or without CoQ10 consumption for 6 weeks. A battery of behavioral tests including open field and Morris water maze tests were done at the end of the sixth week, and then the animals' brains were removed for stereological methods. Our finding indicated that the high dose of Sunset Yellow FCF led to a reduced total volume of mPFC (15.16%), especially in the anterior cingulate cortex (ACC) region (21.96%), along with loss of neurons (32%) and glial cells (37%), which was associated with higher anxiety behavior and loss of spatial memory. However, CoQ10 prevented the neural loss and glial cells, improved anxiety‐like behaviors, and memory impairment. On the other hand, the acceptable daily dose (low dose of Sunset Yellow FCF) did not show a discernible effect on the same parameters. This study showed that the CoQ10 can protect the alteration in mPFC structure and behavioral changes of the rats exposed to high dose of Sunset Yellow FCF.