General anesthetics exposure, particularly prolonged or repeated exposure, is a crucial cause of neurological injuries. Notably, isoflurane (ISO), used in pediatric anesthesia practice, is toxic to the developing brain. The relatively weak antioxidant system at early ages needs antioxidant support to protect the brain against anesthesia. Cerium oxide nanoparticles (CeO-NPs, nanoceria) are nano-antioxidants and stand out due to their unique surface chemistry, high stability, and biocompatibility. Although CeO-NPs have been shown to exhibit neuroprotective and cognitive function-facilitating effects, there are no reports on their protective effects against anesthesia-induced neurotoxicity and cognitive impairments. Herein, Wistar albino rat pups were exposed to ISO (1.5 %, 3-h) at postnatal day (P)7+P9+P11, and the protective properties of CeO-NP pretreatment (0.5 mg/kg, intraperitoneal route) were investigated for the first time. The control group at P7+9+11 received 50 % O (3-h) instead of ISO. Exposure to nanoceria one-hour before ISO protected hippocampal neurons of the developing rat brain against apoptosis [determined by hematoxylin-eosin (HE) staining, immunohistochemistry (IHC) analysis with caspase-3, and immunoblotting with Bax/Bcl2, cleaved caspase-3 and PARP1] oxidative stress, and inflammation [determined by immunoblotting with 4-hydroxynonenal (4HNE), nuclear factor kappa-B (NF-κB), and tumor necrosis factor-alpha (TNF-α)]. CeO-NP pretreatment also reduced ISO-induced learning (at P28-32) and memory (at P33) deficits evaluated by Morris Water Maze. However, memory deficits and thigmotactic behaviors were detected in the agent-control group; elimination of these harmful effects will be possible with dose studies, thus providing evidence supporting safer use. Overall, our findings support pretreatment with nanoceria application as a simple strategy that might be used for pediatric anesthesia practice to protect infants and children from ISO-induced cell death and learning and memory deficits.