It is now well-established that orexins (OXs) and their receptors are involved in the pathophysiology of depression. Considering the evidence indicating the importance of nitric oxide (NO) system in the mood modulation, this study investigated the effect of intraperitoneal (i.p.) administration of orexin 1 (OX1) receptor antagonist -SB334867- alone or in combination with NO agents on depression using the forced swimming test (FST), tail suspension test (TST) and the number of crossings in open-field test (OFT) in mice. Our results indicated that administration of SB334867 at the dose of 0.5 mg/kg decreased the immobility time in the FST without effect on locomotor activity, suggesting an antidepressant-like effect of SB334867. Moreover, l-Arginine (a NO precursor; 750 mg/kg) or L-NAME (a non-selective nitric oxide synthase (NOS) inhibitor, 10 mg/kg) administration by itself decreased the immobility time in the FST. Interestingly, co-administration of a sub-threshold dose of L-NAME, but not l-Arginine, in combination with an ineffective dose of SB334867 produced an antidepressant-like effect in the FST and TST. It should be noted, none of the drugs elicited significant effects on the locomotor activity in the OFT. Altogether, the present data propose that a combination of the sub-effective dose of OX and NO antagonists can be evaluated as an option for the clinical treatment of depression in humans.