Recent evidence suggests cannabinoids as preventive treatment for AD, mainly based on their anti-inflammatory effects. The endocannabinoid system consists of at least two well-characterized cannabinoid receptor (CB) subtypes, CB1 and CB2. The activity of CB2 receptor is implicated in the reduction of proinflammatory molecules in response to harmful stimuli and in the control of neural survival.  In AD postmortem brains, CB2 receptor has been reported to be overexpressed in β-amyloid plaque-associated microglia, suggesting that it could be a therapeutic target. The activation of CB2 receptor has the beneficial effects of inducing cognitive improvement and reducing neuroinflammatory response in two different in vivo models of AD. Recently, the plant metabolite β-caryophyllene was shown to selectively bind to CB2 receptor and act as a full agonist.This report aimed at testing the efficacy of β-caryophyllene on the cognitive deficits, neuroinflammation, and the β-amyloid burden in the APP/PS1 mouse model of AD. The results demonstrate that β-caryophyllene, given orally prevented cognitive impairment in APP/PS1 mice, and this positive cognitive effect was associated with reduced β-amyloid burden in both the hippocampus and the cerebral cortex. Moreover, β-caryophyllene reduced astrogliosis and microglial activation as well as the levels of COX-2 protein and the mRNA levels of the proinflammatory cytokines tumor necrosis factor-α and interleukin-1β in the cerebral cortex. The use of the CB2 antagonist AM630 or the PPARγ antagonist GW9662 significantly reversed the protective effects of β-caryophyllene on APP/PS1 mice. Taken together, these results strongly suggest that the potentially disease modifying effects of β-caryophyllene involves CB2 receptor activation and the PPARγ pathway and suggest β-caryophyllene as an attractive molecule for the development of new drugs with therapeutic potential for the treatment of AD.