Enkephalins, endogenous ligands for delta opioid receptors (DORs), are highly enriched in the nucleus accumbens (NAc). They are implicated in depression but their role in the NAc, a critical brain region for motivated behavior, is not fully investigated. To provide insight into enkephalin function we used a chronic social defeat stress paradigm, where animals are either categorized as susceptible or resilient to stress based on their performance in a social interaction test. Compared to controls, susceptible animals showed reduced enkephalin levels in the NAc. Such decrease in enkephalin levels is not due to a change in mRNA of its precursor protein, proenkephalin, in susceptible mice but is consistent with increased mRNA levels of enkephalinases in the NAc of susceptible animals. Systemic administration of enkephalinase inhibitors or NAc infusion of the DOR agonist, SNC80, caused a resilient outcome to CSDS. Both treatments increased phosphorylation of ERK, which was downregulated by social defeat stress. To further validate these results, we also used Q175 knock-in mice, an animal model of Huntington's disease in which enkephalin levels are reduced in striatum and comorbidity with mood disorders is common. Consistent with data in wild-type mice, Q175 animals showed reduced enkephalin levels in the NAc and enhanced susceptibility to a social defeat stress. Overall, our data implicate that depression-like behavior induced by social defeat stress arises from disrupted DOR signaling resulting from lowered levels of enkephalins, which is partly mediated through elevated expression of enkephalinases.