Neuroinflammation is regarded to be a key mediator in cerebral diseases with attendant cognitive decline. Ferroptosis, characterized by iron-dependent lipid peroxidation, participates in neuroinflammation and cognitive impairment. Recent studies have revealed insulin's neuroprotective effects and involvement in the regulation of numerous central functions. But the effect of insulin on cognitive impairment induced by neuroinflammation has been rarely explored. In this study, we constructed a cognitive impairment model by intracerebroventricular injection of lipopolysaccharide (LPS) and a single dosage of insulin was mixed in the LPS solution to explore the potential mechanisms through which insulin treatment could improve LPS-induced cognitive dysfunction. At 24 h after treatment, we found that insulin treatment significantly improved LPS-induced cognitive decline, neuronal injuries, and blood-brain barrier (BBB) disruption. Insulin treatment could also inhibit the LPS-induced activation of microglia and astrocytes, and the release of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in the hippocampus. Furthermore, insulin treatment inhibited LPS-induced ferroptosis in the hippocampus by decreasing iron accumulation levels, regulating ferroptosis-related proteins including transferrin, glutathione peroxidase 4 (GPX4), ferritin heavy chin 1 (FTH1) and cystine/glutamate antiporter (xCT), inhibiting oxidative stress injuries and lipid peroxidation in the hippocampus. In conclusion, our finding that insulin treatment could alleviate LPS-induced cognitive impairment by inhibiting neuroinflammation and ferroptosis provides a new potential therapeutic method to ameliorate cognitive decline.Copyright © 2023 Elsevier B.V. All rights reserved.