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Graphical abstract Highlights • Role of astaxanthin on hippocampal insulin resistance in rat model of Alzheimer's disease. • Aβ (1–42) peptides enhanced Insulin receptor Substrate-1 S307 phosphorylation. • Astaxanthin reduced Insulin receptor Substrate-1 S307 phosphorylation. • Astaxanthin ameliorated GSK-3β phosphorylation and Aβ (1–42) level. • Astaxanthin showed neuroprotective and anti-amyloidogenic effects in neurohistology. Abstract With the constant failure of the clinical trials continuous exploration of a therapeutic target against Alzheimer's disease (AD) is the utmost need. Numerous studies have supported the hypothesis that central insulin resistance plays a significant role in AD. Serine phosphorylation of Insulin Receptor Substarte-1 (IRS-1) has been found to be a contributing factor in neuronal insulin resistance. Astaxanthin (ASX) is xanthophyll carotenoid which has previously demonstrated significant antidiabetic and neuroprotective actions. In the present study, AD was induced by i.c.v administration of Amyloid-β (1–42) peptides in Wistar rats. After 7 days of recovery, rats were treated with 0.5 mg/kg and 1 mg/kg of ASX orally for 28 days. Behavioral analysis was done in the last week of our experimental study. On the 36th day, rats were sacrificed and their hippocampus were separated from the whole brain, then homogenized and stored for biochemical estimations. ASX significantly and dose-dependently reversed the cognitive and memory impairment, assessed by Morris water maze test and Novel object Recognition test, Aβ (1–42) peptides infused Wistar rats. ASX also significantly attenuated soluble Aβ (1–42) level, IRS-S307 activity, GSK-3β activity, TNF-α level, AChE level, nitrite level and oxidative stress in the hippocampus. Histopathological evaluation, done through H&E and Congo red staining, also demonstrated neuroprotective and anti-amyloidogenic effects of ASX in hippocampus. Our study concludes preventive action of Astaxanthin against hippocampal insulin resistance and Alzheimer's disease complications, supporting potential role of hippocampal insulin resistance targeting against AD. [ABSTRACT FROM AUTHOR]