Abstract: Objective To investigate the antiepileptic effects of the natural κ-opioid receptor (KOR) agonist Salvinorin A (SA) on pilocarpine-induced chronic epileptic mice and to explore the underlying mechanisms.Methods A total of 45 male 8-week-old C57BL/6J mice were randomly divided into four groups: a normal control group, a model control group, a SA low-dose group (0.3 mg/kg), and a SA high-dose group (1.0 mg/kg). The mice were intraperitoneally injected with the corresponding drug or vehicle once daily for two weeks before model induction. On the day of modeling, status epilepticus (SE) was induced by pilocarpine. Seizure-like behaviors were evaluated by the Racine seizure scale. During the chronic epilepsy stage, electroencephalographic (EEG) changes were monitored. Nissl staining was used to assess neuronal damage in the hippocampus. Proteomic analysis was performed to identify protein expression changes in the hippocampus, and Western blot analysis was used to detect the expression of proteins involved in the PTEN-induced kinase 1/Parkin/microtubule-associated protein light chain 3 (PINK1/Parkin/LC3) signaling pathway.Results Compared with the model control group, the high-dose SA group showed a significantly prolonged latency to pilocarpine-induced seizures (P<0.001) and a markedly shortened seizure duration (P<0.001). During the chronic epilepsy stage, hippocampal neuronal damage was alleviated. Proteomic analysis indicated that mitophagy was deeply involved in the antiepileptic mechanism of SA. Furthermore, the levels of p-Parkin and LC3 proteins in the PINK1/Parkin/LC3 pathway in the hippocampus of mice in the high-dose SA group were significantly reduced (P<0.05).Conclusions Salvinorin A exerts significant antiepileptic effects by inhibiting the activation of the PINK1/Parkin/LC3 signaling pathway in the hippocampus of chronic epileptic mice, thereby reducing mitophagy and hippocampal neuronal damage.