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Introduction: Celastrus paniculatus seed oil, commonly known as Malkangni or Jyotishmati, was&nbsp;in use from time immemorial to treat brain related disorders. Celastrus paniculatus seed oil has&nbsp;significant antidepressant-like activity in chronic unpredictable stressed mice. The present study was&nbsp;undertaken to evaluate the antidepressant-like effect of Celastrus paniculatus seed oil in unstressed&nbsp;mice and to explore its mechanism of action. Methods: The seed oil (50, 100, and 200 mg/kg, PO) and fluoxetine per se were administered for&nbsp;14 successive days to Swiss young albino mice. On the 14th day, 60 min after drug administration,&nbsp;animals were subjected to Tail Suspension Test (TST) and Forced Swim Test (FST). The mechanism&nbsp;of action was also studied. Results: The oil significantly decreased immobility period of mice in both tail suspension test and&nbsp;forced swim test, indicating its significant antidepressant-like activity. The efficacy was found to be&nbsp;comparable to fluoxetine (P<0.0001). ED50 value of celastrus seed oil using FST and TST were 17.38&nbsp;and 31.62 mg/kg, respectively. The oil did not show any significant effect on locomotor activity. It&nbsp;significantly inhibited brain MAO‒A activity and decreased plasma corticosterone levels. Sulpiride (selective D2-receptor antagonist), p-CPA (tryptophan hydroxylase inhibitor), and baclofen (GABAB&nbsp;agonist) significantly attenuated the oil-induced antidepressant-like effect, when assessed during TST.&nbsp; Discussion: Celastrus paniculatus seed oil produced significant antidepressant-like effect in mice&nbsp;possibly through interaction with dopamine D2, serotonergic, and GABAB receptors as well as&nbsp;inhibition of MAO‒A activity and decrease in plasma corticosterone levels.