Background: Vitamin B6 is a cofactor for various enzymes that are involved in neurotransmitter production. It has been shown that vitamin B6 administration reduces immobility time in mice forced swimming test (FST), which suggests potential antidepressant activity in humans. The aim of this study was to observe the possible involvement of the noradrenergic system in the antidepressant effects of vitamin B6 during FST in mice. Material and methods: Each of the following drugs was administered with vitamin B6: a tricyclic antidepressant (imipramine), α1 adrenoceptor antagonist (prazosin), α2 adrenoceptor antagonist (yohimbine), and β adrenoceptor antagonist (propranolol) and α-methyl-p-tyrosine (AMPT), a selective inhibitor of the enzyme tyrosine hydroxylase. Results: The antidepressant effect of vitamin B6 (100 mg/kg) was increased by adding imipramine (5 mg/kg), prazosin (1 mg/kg) to the treatment and slightly by propranolol (2 mg/kg). Yohimbine (1 mg/kg), to some extent, reversed vitamin B6 effects although not completely compared with the control group, whereas AMPT (100 mg/kg) administration absolutely reduced vitamin B6 antidepressant effect during the FST. Conclusion: This study provides evidence indicating that the antidepressant-like effect of vitamin B6 in the FST is dependent on its interaction with α and β adrenoceptors and the noradrenergic system plays a critical role in its antidepressant benefits.