Objective: Maternal separation as an epigenetic agent provokes a severe change in the brain such as inflammation response, which is a key risk factor for the progression of autism spectrum disorders (ASD). Methods: This study evaluated the preventive effect of hypericin on maternal separation-induced cognitive deficits and hippocampal inflammation. Here, we reported that pups are subjected to maternal separations for 1 h per day from postnatal days (PND) 1–9 displayed apparent memory impairment in young rats (postnatal day 34) compared to controls group. Furthermore, the maternal separation significantly increased inflammation factors in hippocampus area. Anti-inflammation constituent shed light on treating ASD. Results: In this study, we found that, treatment with hypericin (10 and 50 mg/kg) significantly suppresses expression of hippocampal interleukin-6 (IL-6) and tumor necrosis factor α (TNF- α) in maternal separation rat model. Also, we found that hypericin prevented the decrease of hippocampal dopamine level in offspring of maternal separation rats. Conclusion: The data indicated that hypericin may play a neuroprotective role in hippocampal cell and ameliorates dysfunctions in memory and level of inflammation factor in this autism model. Thus, hypericin could be used as an intervention for treating ASD.