Background and PurposeStress exposure produces excitotoxicity and neuroinflammation, contributing to the cellular damage observed in stress‐related neuropathologies. The endocannabinoids provide a homeostatic system, present in stress‐responsive neural circuits. Here, we have assessed the possible regulatory role of cannabinoid CB2receptors in stress‐induced excitotoxicity and neuroinflammation.Experimental ApproachWe used wild type (WT), transgenic overexpressing CB2receptors (CB2xP) andCB2receptor knockout (CB2‐KO) mice exposed to immobilization and acoustic stress (2 h·day−1for 4 days). TheCB2receptor agonistJWH‐133 was administered daily (2 mg·kg−1, i.p.) toWTandCB2‐KOanimals. Glutamate uptake was measured in synaptosomes from frontal cortex; Western blots and RT‐PCR were used to measure proinflammatory cytokines, enzymes and mediators in homogenates of frontal cortex.Key ResultsIncreased plasma corticosterone induced by stress was not modified by manipulating CB2receptors.JWH‐133 treatment or overexpression of CB2receptors increased control levels of glutamate uptake, which were reduced by stress back to control levels.JWH‐133 prevented the stress‐induced increase in proinflammatory cytokines (TNF‐α and CCL2), inNF‐κB, and inNOS‐2 andCOX‐2 and in the consequent cellular oxidative and nitrosative damage (lipid peroxidation).CB2xPmice exhibited anti‐inflammatory or neuroprotective actions similar to those inJWH‐133 pretreated animals. Conversely, lack of CB2receptors (CB2‐KOmice) exacerbated stress‐induced neuroinflammatory responses and confirmed that effects ofJWH‐133 were mediated throughCB2receptors.Conclusions and ImplicationsPharmacological manipulation of CB2receptors is a potential therapeutic strategy for the treatment of stress‐related pathologies with a neuroinflammatory component, such as depression.