Social isolation stress (SIS) as a type of chronic stress could induce depressive- and anxiety-like behaviors. Our study evaluates the role of opioid system on negative behavioral impacts of SIS in male NMRI mice. We investigated effects of morphine, a nonselective opioid receptor (OR) agonist, naltrexone (NLX), an OR antagonist, naltrindole (NLT), a delta opioid receptor (DOR) antagonist, SNC80, a DOR agonist, U-69593, a kappa opioid receptor (KOR) agonist, nor-Binaltorphimine, a selective KOR antagonist and cyprodime hydrochloride a selective mu opioid receptor (MOR) antagonist on depressive- and anxiety-like behaviors. Using RT-PCR we evaluated ORs gene expression in mice brain. Our findings showed that SIS induced anxiety- and depressive-like behavior in the forced swimming test, open field test, splash test and hole-board test. Moreover, administration of SNC-80 significantly mitigated anxiety- and depressive-like behaviors. NLT decreased grooming-activity in the splash test. Excitingly, administration of agents affecting KOR failed to alter the negative effects of SIS. RT-PCR demonstrated that MOR and KOR gene expression decreased in socially isolated mice; however, SIS did not affect DORs expression. Our findings suggest that SIS at least in part, probably via altering endogenous opioids particularly MORs and KORs but not DORs mediated negative impacts on behavior; also, it could be concluded that DORs might be considered as a novel target for studying depression and anxiety.