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The present study investigated the antidepressant-like potential of a functionalized 3-selanyl benzo[ b ]furan (SeBZF) in male Swiss mice. To evaluate possible antidepressant-like actions, the compounds SeBZF 1-5 (50 mg/kg, intragastric, i.g., route) were acutely screened in the tail suspension tests (TSTs). The compound 3-((4-methoxyphenyl)selanyl)-2-phenylbenzofuran (SeBZF 3 ) was then selected. Dose-response and time-response curves revealed that SeBFZ 3 exerts antidepressant-like effects in the TST (5-50 mg/kg) and forced swimming test (FST; 50 mg/kg). Additional tests demonstrated that pretreatment with receptor antagonists WAY100635 (5-HT 1A ; 0.1 mg/kg, subcutaneous route), ketanserin (5-HT 2A/C ; 1 mg/kg, intraperitoneal, i.p.), or ondansetron (5-HT 3 ; 1 mg/kg, i.p.) blocked the SeBZF 3 antidepressant-like effects (50 mg/kg) in the TST. In addition, the coadministration of subeffective doses of SeBZF 3 (1 mg/kg, i.g.) and fluoxetine (a selective serotonin reuptake inhibitor; 5 mg/kg, i.p.) produced synergistic action. A high dose of SeBZF 3 (300 mg/kg) did not produce oral acute toxicity. The present results provide evidence for the antidepressant-like action of SeBZF 3 and its relative safety, as well as predict the possible interactions with the serotonergic system, aiding in the development of novel options to alleviate psychiatric disabilities.