Antidepressants that target the monoaminergic system are prescribed most frequently in the psychiatric practice. However, not all patients benefit from their use. It is generally known that co-administration of agents aiming distinct targets may increase the therapeutic effect and at the same time permit dose reduction. A number of studies have suggested a CB1 receptor-mediated interplay between the endocannabinoid system and the monoaminergic signalling in the brain. Therefore, we wanted to determine whether the CB1 receptor ligands (oleamide and AM251) affect the activity of the common antidepressant drugs that influence the monoaminergic system. In order to determine the antidepressant-like activity, the forced swim test and the tail suspension test in mice were used. Additionally, brain concentrations of the tested antidepressants were evaluated by the HPLC method. Concurrent intraperitoneal administration of per se inactive doses of oleamide (5 mg/kg) or AM251 (0.25 mg/kg) and imipramine (15 mg/kg), escitalopram (2 mg/kg), and reboxetine (2.5 mg/kg) reduced the immobility time of animals in the forced swim test and the tail suspension test. The observed effect was not associated with hyperlocomotion of animals. Summarizing, the outcomes of the present study demonstrated that modulation (i.e., activation or inhibition) of the CB1 receptor function potentiates the antidepressant activity of common drugs that influence the monoaminergic (serotonergic and noradrenergic) system. This effect is most probably predominantly pharmacodynamic in nature instead of pharmacokinetic.