Background: Depression is a state of mental illness characterized by long-lasting moods of desolation. Typical to atypical antidepressants are available in modern medicine for depression therapy, but the side effects are still questionable. Aqueous extract of Abelmoschus esculentus seeds (AEAES) from the Okra has been chosen for the study. AEAES has already been shown to exhibit an antidepressant-like effect, but there is no information about its mechanism. The current study has studied the monoaminergic and opioid systems' involvement in the antidepressant effect of AEAES. Methods:The current study has shown the signal for the role of nor-adrenergic and serotonergic systems in the antidepressant activity of AEAES in mice using the Forced swim test (FST). Swiss Albino female mice were treated with vehicle AEAES (200 mg/kg) orally, and different types of receptor antagonists were used to demonstrate the mechanism of action of an AEAES. Results: The antidepressant action exhibited by AEAES was obliterated by the pre-treatment of mice with p-chlorophenylalanine (100 mg/kg, i.p., serotonin synthesis inhibitor), Ketanserin (5 mg/kg, i.p., a 5HT 2A/2B antagonist) and Prazosin (1 mg/kg, i.p., an α 1 blocker) but the effect was not abolished with Pindolol (10 mg/kg, i.p., 5HT 1A/1B antagonist), Ondansetron (1 mg/kg, i.p., 5HT 3 antagonist), Yohimbine (1 mg/kg, i.p., an α 2 blocker) and Naloxone (1 mg/kg, i.p., an opioid antagonist). Conclusions: The current study delivers evidence that the antidepressant activity of AEAES in FST is mediated through the interaction with the serotonergic receptor (5-HT 2A/2B ) and noradrenergic receptor (α-1 adrenoceptor) without influencing the opioid receptors.INTRODUCTION: Depression, the most common affective or mood disorder along with mania, is considered a devastating disorder with disturbing mood.