Background and aim Campomanesia xanthocarpa Berg. (Myrtaceae) present several pharmacological actions, but there are no reports on its antidepressant-like potential. This study investigated the antidepressant-like effect and mechanism of action of Campomanesia xanthocarpa seeds extract obtained from supercritical CO2 (40 °C, 250 bar). Experimental procedure Mice were orally treated with the extract 1 h before the TST. To investigate the involvement of the monoaminergic system in the antidepressant-like activity of the extract, pharmacological antagonists were administered prior to the acute oral administration of the extract (60 mg/kg). Also, the interaction of the extract with antidepressants was assessed in the tail suspension test (TST). The in vitro inhibitory potential of C. xanthocarpa seeds extract towards MAO A and MAO B enzymes was tested in vitro. Results and conclusion Animals treated with Campomanesia xanthocarpa seeds extract showed a significant reduction in the immobility time in the TST. Mice pretreatment with SCH23390, sulpiride, prazosin, yohimbine, and p-chlorophenylalanine prevented the anti-immobility effect of the extract in the TST. The combined administration of sub-effective doses of the extract with imipramine, bupropion and fluoxetine significantly reduced mice immobility time in the TST. The extract showed MAO A inhibitory activity (IC50 = 151.10 ± 5.75 μg/mL), which was greater than that toward MAO B (IC50 > 400 μg/mL). The extract of Campomanesia xanthocarpa seeds obtained by supercritical CO2 shows antidepressant-like activity, which relies on the activation of the monoaminergic neurotransmission (serotoninergic, dopaminergic and noradrenergic), suggesting that this species might represent a resource for developing new antidepressants.