Up to 45% of patients surviving from transient global cerebral ischemia (GCI) after cardiac arrest develop post-global cerebral ischemia depression (PGCID), but how to treat PGCID is clinically unknown. Here we find that cannabinoid type-1 receptor (CBR) antagonists, CBR knockout and endocannabinoid (eCB) synthesis inhibition block acute stress-induced PGCID. Application of acute stress to GCI mice increases CBR activity from ventromedial prefrontal cortical (vmPFC) terminals synapsing with the basolateral amygdala (BLA) neurons, indicating the involvement of increased vmPFC-BLA synaptic eCB signaling in PGCID induction. This idea is supported by findings that optogenetic activation of CBRs in vmPFC-BLA projections mimics stress effects to induce PGCID, which is blocked by knock-down of eCB biosynthesis enzyme genes in vmPFC-BLA synapses. Interestingly, GCI mice show decreased mRNA expression of eCB degradation enzymes in vmPFCs without significant changes on mRNA expression of eCB biosynthesis and degradation enzymes in BLA cells. Thus, over-expression of eCB degradation enzymes in vmPFC cells innervating BLA neurons or activation of vmPFC-BLA projections blocks stress effects to induce PGCID. Our findings suggest that decreased eCB degradation and subsequent stress-increased eCB signaling in vmPFC-BLA circuits participate in the mechanism of PGCID, which can be treated clinically by eCB signaling interference systemically or in vmPFC-BLA circuits.