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Depression, a multifactorial neuronal disorder with high morbidity/mortality, is associated with psychological, psychosocial, hereditary, and environmental etiologies, where reactive species exert pathophysiological functions. Anacardic acid (AA), a natural compound obtained from cashew nut liquid, has several pharmacological activities, including antioxidant and anticonvulsant. The aim of the present study was to evaluate the antidepressant‐like effect of AA and the involvement of serotonergic, noradrenergic, and L‐arginine–nitric oxide (NO) in tail suspension and forced swim tests and, more so, to investigate its antioxidant effect in Saccharomyces cerevisiae and in male Swiss mice (n = 8). In order to identify the antidepressant mechanisms, AA (10, 25, or 50 mg/kg, p.o.) was given 30 min before clonidine (2‐adrenergic receptor agonist), L‐arginine (NO precursor), propranolol (β‐adrenergic receptor antagonist), and several other agonists or antagonists used. On the other hand, clonidine, noradrenoreceptor, noradrenaline, and L‐arginine were used to identify the antidepressant mechanisms. Results suggest that AA exerts antidepressant‐like activity, especially at higher doses, possibly by inhibiting serotonin and 5HT‐1A reuptake receptors and by inhibiting NO synthetase and guanylyl cyclase enzymes. Additionally, AA exhibited antioxidant effect in S. cerevisiae. This antioxidant capacity may be linked to its antidepressant‐like effect but does not interact with α‐ and β‐adrenoceptor receptors. In conclusion, AA may be used as a promising agent to treat depression, especially which arises from oxidative stress.