Objective: The present study aimed to investigate the effect of Hypericum perforatum extract on amikacin-induced kidney disease in rats. Methods: About 28 female Spraque-Dawley rats were separated into groups. The control, amikacin, amikacin+ H. perforatum extract, and H. perforatum extract groups were given intraperitoneally 1 mL of serum physiologic, amikacin (1.2 g/kg), H. perforatum extract (50 mg/kg) + amikacin (1.2 g/kg), and H. perforatum extract (50 mg/kg), respectively. On the third day, serum blood urea nitrogen, creatinine, malondialdehyde, superoxide dismutase, catalase, glutathione peroxidase, histopathology, and apoptosis were explored in kidney tissue. Results: The serum blood urea nitrogen and creatinine levels were higher in H. perforatum extract-pretreated amikacin group than in the other groups. Kidney malondialdehyde levels which showed oxidative injury were lowest in the serum physiologic group and highest in amikacin and amikacin+H. perforatum extract groups. Anti-oxidative enzyme (superoxide dismutase, catalase, glutathione peroxidase) levels decreased more in amikacin and amikacin+H. perforatum extract groups than serum physiologic (control) and H. perforatum extract groups. Histopathological damage scores of the amikacin+H. perforatum extract group were higher than the other groups. Proximal tubular tissue necrosis was observed in all of the rats in amikacin and amikacin+H. perforatum extract groups. Amikacin and amikacin+H. perforatum extract groups demonstrated the highest apoptotic index percentage. Conclusion: We found that H. perforatum extract increased kidney injury mostly through oxidative damage and induction of apoptosis.