Background: Cissus quadrangularis has been used for cure of various ailments that includes bone cracks, frail bones (osteoporosis), scurvy, malignant growth, annoyed stomach, hemorrhoids, peptic ulcer sickness, excruciating menstrual periods, asthma, jungle fever (malaria), and mental distress. Specially it is used for bone healing properties. According to this background, the aim of the study was to evaluate the antidepressant-like effect of the ethanolic extract of Cissus quadrangularis (EECQ) in different behavioral models such as forced swimming test (FST) and tail suspension test (TST) on mice after two weeks treatment. Methods: Mice were divided into six groups (n=6/group): control group (normal saline), stress control (normal saline), standard group where Imipramine (15mg/kg) was used as standard drug and three test groups where three doses of ethanolic extract of C. quadrangularis (EECQ) (100, 250, and 350mg/kg) was used for two weeks treatment. All the medication and test samples were managed by means of gavage through oral course. To evaluate the antidepressant like impact of EECQ forced swim test (FST) and tail suspension test (TST) have been done in mice. Results: The outcomes demonstrated that a solid and dose-dependent antidepressant effects in various mice models. The main findings of the EECQ significantly decreased the duration of immobility times in the forced swimming test (p<0.5). Likewise, the extract significantly decreased the immobility time in the tail suspension test (p<0.5) when compared against stress control as well as against imipramine which was used as a standard. Conclusion: The present results clearly demonstrate that the ethanolic extract of C. quadrangularis possesses antidepressant-like activity in the animal behavioral models. Cissus quadrangularis plant can be used for the treatment of neurological disorders and may be recommended as a supplement for the antidepressant activity.