Depression is one the world leading global burdens leading to various comorbidities. Lithium as a mainstay in the treatment of depression is still considered gold standard treatment. Similar to lithium another agent agmatine has also central protective role against depression. Since, both agmatine and lithium modulate various effects through interaction with NMDA receptor, therefore, in current study we aimed to investigate the synergistic antidepressant-like effect of agmatine with lithium in mouse force swimming test. Also to know whether if such effect is due to interaction with NMDA receptor. In our present study we found that when potent dose of lithium (30 mg/kg) was administered, it significantly decreased the immobility time. Also, when subeffective dose of agmatine (0.01 mg/kg) was coadministered with subeffective dose of lithium (3 mg/kg), it potentiated the antidepressant-like effect of subeffective dose of lithium. For the involvement of NMDA receptor in such effect, we administered NMDA receptor antagonist MK-801 (0.05 mg/kg) with a combination of subeffective dose of lithium (3 mg/kg) and agmatine (0.001 mg/kg). A significant antidepressant-like effect was observed. Furthermore, when subeffective dose (50 and 75 mg/kg) of NMDA was given it inhibited the synergistic effect of agmatine (0.01 mg/kg) with lithium (3 mg/kg). Hence, our finding demonstrate that agmatine have synergistic effect with lithium which is mediated by NMDA receptor pathway