Iron-dependent lipid peroxidation-induced ferroptosis has been implicated in the pathogenesis of cerebral ischemia. Ischemia-reperfusion (I/R) contributes to cognitive dysfunction. Chromobox7 (CBX7) was upregulated in neural progenitor cells, followed by hypoxia and ischemia, and the suppression of CBX7 protected against renal and cerebral I/R injuries. However, the role of CBX7 in ferroptosis and cognitive dysfunction in rats with cerebral ischemia has not yet been reported. In our study, first, rats with cerebral I/R were established through middle cerebral artery occlusion (MCAO). Intracerebroventricular injection of shRNA targeting CBX7 (sh-CBX7) enhanced brain water content, and reduced neurological deficit scores and infarct size in rats post MCAO. Second, rats were subjected to 4 trials per day for 4 consecutive days in a Morris water maze. The time to find the platform in with 1 min was recorded as escape latency. On day 5, the platform was removed to conduct a spatial probe test. Rats were given 1 min to find the position of the platform, and the times for crossing the target within 1 min were recorded. Crossing the platform time is the time spent in each quadrant. Data from the Morris water maze showed that cognitive dysfunction in ischemic rats was ameliorated by the injection of sh-CBX7, which decreased the swimming distance and escape latency of ischemic rats, increased the times for crossing the target and platform in the maze. Moreover, injection of sh-CBX7 down-regulated levels of MDA and ROS, while it up-regulated SOD and GSH-Px to repress the oxidative stress. Third, knockdown of CBX7 in ischemic rats decreased the concentration of the ferric ions and the protein expression of transferrin receptor 1 (TFR1), but enhanced the solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4), resulting in the inhibition of ferroptosis. Lastly, expressions of Nrf2, HO-1 and NAD(P)H:quinone oxidoreductase 1 (NQO1) were up-regulated in ischemic rats post sh-CBX7 injection. In conclusion, suppression of CBX7 attenuated I/R injury, improved cognitive dysfunction and inhibited ferroptosis through the activation of the Nrf2/HO-1 signaling pathway.