Background <p>FNDC5/Irisin is a key regulator of cognitive function, but its role in diabetes-associated cognitive decline (DACD) and underlying mechanisms remain unclear. This study aimed to investigate the expression and mechanistic effects of FNDC5/Irisin in DACD.</p> Methods <p>STZ-induced diabetic rats were evaluated for cognitive deficits using the Morris water maze. Hippocampal and serum FNDC5/Irisin levels were measured during DACD progression. Hippocampus-specific FNDC5/Irisin overexpression was achieved via an adeno-associated virus. Transcriptomic and untargeted metabolomic analyses were performed to identify potential signaling pathways. In vitro experiments using Fndc5 knockdown and recombinant Irisin further validated the mechanisms.</p> Results <p>FNDC5/Irisin was reduced in the hippocampus of diabetic rats, correlating with cognitive impairment. Overexpression restored neuronal structure and improved cognitive performance. Multi-omics integration indicated that FNDC5/Irisin mitigates DACD via modulation of oxidative stress, neuroinflammation, and cAMP signaling. Mechanistically, FNDC5/Irisin suppressed oxidative stressmarked by increased oxidized glutathione, arachidonic acid, 2-hydroxy-dAMP, hydroquinone, and xanthine, and decreased riboflavin and glial activation, regulated inflammatory responses (downregulating pro-inflammatory cytokines IL-1β, TNF-α, IL-6, IFN-γ, and KC/GRO, while upregulating anti-inflammatory cytokines IL-4, IL-10, and IL-13). It also activated cAMP signaling via the integrin αVβ5 receptor, enhancing dendritic complexity, spine density, and synaptic plasticity.</p> Conclusions <p>This study demonstrates for the first time that FNDC5/Irisin is a critical modulator of DACD, alleviating cognitive deficits through interplay among oxidative stress, inflammation, and synaptic plasticity. These findings provide novel mechanistic insights and highlight FNDC5/Irisin as a potential therapeutic target for DACD.</p>