Numerous studies have indicated a close association between gut microbiota dysbiosis, inflammation, and cognitive impairment, highlighting their crucial role in the aging process. 2-(3,4-Dihydroxyphenyl)ethyl 3-hydroxybutanoate (HTHB), a novel derivative of hydroxytyrosol, known for its metabolic and anti-inflammatory properties, was investigated for its effects on memory, inflammation, and gut microbiota in senescence-accelerated mouse prone 8 mice. The study employed behavioral testing, biochemical detection, and 16S RNA analysis. Results revealed that HTHB mitigated memory decline and lymphocyte aberrance, reduced inflammation in the brain cortex, intestine and peripheral system, and modulated gut microbiota dysbiosis. Interestingly, the cognitive function and serum inflammation of mice significantly correlated with differences in gut microbiota in senescence-accelerated mouse prone 8 mice. Furthermore, HTHB treatment exhibited an enhancement of gut barrier integrity in colon tissue in SAMP8 mice. In vitro experiments using HCT116 and DLD1 cells further evidenced that HTHB rescued the tight junction protein levels impaired by lipopolysaccharide. These findings demonstrate that HTHB effectively ameliorates cognitive dysfunction in aged mice, by modulating gut microbiota, suppressing inflammation, and promoting intestinal barrier integrity. This highlights the potential of HTHB as a therapeutic agent for age-related cognitive loss.