〔Abstract〕 To investigate the effect and mechanism of simvastatin pretreatment on kidney ischemia reperfusion injury (IRI) in mice. Methods Fifteen male C57BL/6 mice aged 6-8 weeks were divided into three groups: Sham operation group (Sham group), kidney IRI group (IR group), and simvastatin pretreatment+kidney IRI group (SIM group). Hematoxylin-eosin (HE) staining of kidney tissue and detection of serum creatinine (SCr) and lactate dehydrogenase (LDH) were used to evaluate kidney injury. The levels of superoxide dismutase (SOD), reduced glutathione (GSH), malondialdehyde (MDA) and reactive oxygen species (ROS) were detected to evaluate oxidative stress. The contents of ferrous iron (Fe2+) and ferric iron (Fe3+) in kidney tissue were detected, and the morphological changes of mitochondria were observed by transmission electron microscope. The relative expression levels of Kruppel-like factor 2 (KLF2), glutathione peroxidase 4 (GPX4), solute carrier family 7 member 11 (SLC7A11), and acyl-coa synthetase long chain family member 4 (ACSL4) protein in kidney tissue were detected to evaluate ferroptosis. Results Compared with the IR group, the SIM group had significantly reduced renal tubular injury and decreased contents of Scr and LDH in serum (P < 0.001). It also showed increased expression of SOD and GSH and decreased expression of MDA and ROS (P < 0.01). Simvastatin pretreatment reduced the contents of Fe2+ and Fe3+ in the tissues (P < 0.01) and alleviated mitochondrial damage. It also promoted the expression of KLF2 (P < 0.01), up- regulated the expression of ferroptosis-related protective proteins GPX4 and SLC7A11, and down-regulated the expression of ferroptosis-related damage protein ACSL4 (P < 0.05).