This study investigated effects of resveratrol on neuroprotection, cognitive impairment, and neuropathology in APP/PS1 mice. Past studies have shown production of Aβ in AD Tg mice is reduced by the overexpression of Sirtuin 1 (SIRT1) and is increased by knocking out SIRT1 in the brain. Resveratrol, a naturally occurring polyphenol mainly found in grapes and red wine, has been reported as a caloric restriction (CR) mimetic with potential anti-aging properties. The most widely accepted mechanistic hypothesis is that resveratrol’s effects, in the same way as CR, are driven through SIRT1 regulation. Resveratrol also activates AMPK, which also regulates insulin sensitivity and mitochondrial biogenesis. This study showed long-term resveratrol treatment significantly prevented memory loss as measured by the object recognition test. Moreover, resveratrol reduced the amyloid burden and increased mitochondrial complex IV protein levels in mouse brain. These protective effects of resveratrol were mainly mediated by increased activation of SIRT1 and AMPK pathways in mice. However, an increase has been observed in IL1  and TNF gene expression, indicating that resveratrol promoted changes in inflammatory processes, although no changes were detected in other key actors of the oxidative stress pathway. Taken together, these findings suggest that resveratrol is able to reduce the harmful process that occurs in APP/PS1 mouse hippocampus, preventing memory loss.