Introduction: Diminished brain insulin sensitivity is associated with reduced cognitive function. Docosahexaenoic acid (DHA) is known to maintain normal brain function.Objectives: This study aimed to determine whether DHA impacts hippocampal insulin sensitivity and cognitive function in aged rats fed a high-fat diet (HFD).Methods: Eight-month-old female Sprague-Dawley rats were randomly divided into three groups (n = 50 each). Rats in the aged group, HFD group, and DHA treatment group received standard diet (10 kcal% fat), HFD (45 kcal% fat), and DHA-enriched HFD (45 kcal% fat, 1% DHA, W/W) for 10 months, respectively. Four-month-old female rats (n = 40) that received a standard diet served as young controls. Neuroinflammation, oxidative stress, amyloid formation, and tau phosphorylation in the hippocampus, as well as systemic glucose homeostasis and cognitive function, were tested.Results: DHA treatment relieved a block in the insulin signaling pathway and consequently protected aged rats against HFD-induced hippocampal insulin resistance. The beneficial effects were explained by a DHA-induced decrease in systemic glucose homeostasis dysregulation, hippocampal neuroinflam-mation and oxidative stress. In addition, DHA treatment broke the reciprocal cycle of hippocampal insulin resistance, Ab burden, and tau hyperphosphorylation. Importantly, treatment of model rats with DHA sig-nificantly increased their cognitive capacity, as evidenced by their increased hippocampal-dependent learning and memory, restored neuron morphology, enhanced cholinergic activity, and activated cyclic AMP-response element-binding protein.Conclusion: DHA improves cognitive function by enhancing hippocampal insulin sensitivity. (c) 2023 The Authors. Published by Elsevier B.V. on behalf of Cairo University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).