Ferroptosis is characterized by excessive accumulation of iron and lipid peroxides, which are involved in ischemia, reperfusion-induced organ injury, and stroke. Propofol, an anesthetic agent, has neuroprotective effects due to its potent antioxidant, anti-ischemic, and anti-inflammatory properties. However, the relationship between propofol and ferroptosis is still unclear. In the current study, we elucidated the role of ferroptosis in the neuroprotective effect of propofol in mouse brains subjected to cerebral ischemia reperfusion injury (CIRI). Ferroptosis was confirmed by Western blotting assays, transmission electron microscopy, and glutathione assays. Propofol regulated Nrf2/Gpx4 signaling, enhanced antioxidant potential, inhibited the accumulation of lipid peroxides in CIRI-affected neurons, and significantly reversed CIRI-induced ferroptosis. Additionally, Gpx4 inhibitor RSL3 and Nrf2 inhibitor ML385 attenuated the effects of propofol on antioxidant capacity, lipid peroxidation, and ferroptosis in CIRI-affected neurons. Our data support a protective role of propofol against ferroptosis as a cause of cell death in mice with CIRI. Propofol protected against CIRI-induced ferroptosis partly by regulating the Nrf2/Gpx4 signaling pathway. These findings may contribute to the development of future therapies targeting ferroptosis induced by CIRI.