Abstract <p>Vitamin C, a crucial antioxidant, plays a significant role in various physiological processes like antioxidation, anti-inflammation, and neuroprotection. Recent studies have unveiled its ability to modulate nervous system by regulating autophagy, suggesting potential applications in treating neurological diseases. This study explored how vitamin C influenced neuronal injury and cognitive impairment induced by lithium chloride–pilocarpine hydrochloride in epileptic rats. Additionally, it seeks to elucidate the antioxidant’s mechanism of action by examining its impact on autophagy regulation. Sprague-Dawley (SD) rats were divided into four groups: vitamin C pretreatment (500 mg/kg of vitamin C via gavage for seven days preceding modeling), vitamin C treatment (500 mg/kg of vitamin C via gavage once after modeling), SE (status epilepticus), and control group. SE rat model was established using lithium chloride–pilocarpine hydrochloride. Cerebral activity was assessed with electroencephalogram (EEG); epilepsy susceptibility was monitored using pentetrazol; cognitive impairment was measured by Morris Water Maze. Neuronal injury was evaluated with hematoxylin–eosin (HE) staining and Nissl staining. Autophagy-related protein expression (Atg7, Atg16L1, and Beclin1) in rat hippocampal tissue was detected using Western Blot and immunofluorescence staining. Both vitamin C treatment and pretreatment groups exhibited reduced seizure frequency, decreased EEG abnormalities, lower epilepsy susceptibility, ameliorated cognitive impairment, less neuronal injury, and lower autophagy-related protein expression compared to the SE group. Vitamin C has the potential to regulate autophagy by modulating autophagy-related protein expression, reducing seizure frequency, improving cognitive impairment and ameliorating neuronal injury in epileptic rats, making it a potential option for clinical applications.</p>