It has been found that dysregulation in the orexin/hypocretin (Ox/HCRT) neuropeptide system in the lateral hypothalamus (LHA) is known to affect sleep disorder, depression and motor activities. However, to date there is no common agreement regarding the resulting specific changes induced in the Ox system. In this study, we inject corticosterone to produce stress-induced depressed mice and investigate the Ox neuronal and corresponding behavioural changes. Different doses (10, 20, 50 mg/kgbw) of corticosterone were injected in adult mice, and then were tested in the open field test, forced swim test, tail suspension test, elevated plus maze test and motor activity measurements to validate the depressed animal model. Significant dose-dependent behavioural changes were observed in correlation with the doses of corticosterone. The effect is most significant and robust in the high 50 mg/kgbw dose group five weeks after injection. Interestingly, we found on average a reduction in motor activity during the 12-hour dark phase (awake) of the depressed mice and no significant change during the light phase (asleep). Finally, using confocal microscopy, immunofluorescence (IF) analysis shows a significant increase (∼20%) in the number of Ox neurons in the LHA of the depressed mice as compared to the age-matched controls. This study suggests that an increase in Ox neuronal signaling may be functionally linked to high and prolonged external stress-induced depression.