Background <p>Age-related cognitive decline poses a growing clinical burden, with mitochondrial oxidative stress recognized as a key mediator. Sirtuin 3 (SIRT3), a mitochondrial deacetylase, is a potential regulator of redox balance, but its role in hippocampal function and cognitive aging, particularly its translational potential, remains unclear.</p> Methods <p>We used D-galactose (D-gal)-treated mice (150&#xa0;mg/kg/day for 8 weeks) to model accelerated aging and neuron-specific SIRT3 knockout (SIRT3^cKO) mice. Transcriptomic profiling, behavioral tests, electrophysiological recordings, and mitochondrial analyses were performed. Therapeutic potential was assessed via intrahippocampal AAV-SIRT3 overexpression.</p> Results <p>D-gal induced memory deficits, disrupted hippocampal theta oscillations, and mitochondrial degeneration, with transcriptomics identifying SIRT3 as the sole mitochondrially localized differentially expressed gene. SIRT3^cKO mice recapitulated these deficits, showing elevated ROS, reduced ATP, aberrant Hif-1α activity, and synaptic/theta rhythm impairments. AAV-SIRT3 overexpression reversed D-gal-induced pathology, which was manifested by the restoration of SOD2 activity, mitochondrial crista density, and theta power, as well as the attenuation of cellular senescence.</p> Conclusions <p>SIRT3 is a critical regulator of hippocampal mitochondrial redox homeostasis. Augmenting hippocampal SIRT3 represents a promising therapeutic strategy for age-related cognitive impairment, supporting the translation of these findings to clinical interventions for neurological decline.</p>