Background: The aim of this study is to compare the antidepressant-like effects of NMDA anta-gonists (zinc sulfate, amantadine, and folic acid) with venlafaxine. Materials and Methods: Ninety-six male Swiss Albino mice were used in the experiments and divided into experimental groups. To assess depression-like behaviors in the animals, the forced swim test was performed. The effects of the drugs on locomotor activity were measured using the open field test. Results: No differences were found between venlafaxine, folic acid, or zinc sulfate when admi-nistered alone in the experimental depression model. When administered in combination, the highest antidepressant-like effect was observed in the zinc-amantadine combination and the zinc sulfate-amantadine-folic acid combination. When venlafaxine and folic acid were adminis-tered together, the antidepressant-like effect was greater compared to other venlafaxine com-binations. Conclusions: The use of these combinations in the treatment of depression is important for the enhancement of antidepressant efficacy.