It was aimed to synthesize some novel piperidine derivatives and investigate their antidepres-sant-like activities, in this study. Targeted compounds were obtained by reacting 1-(4-(substitutedpiper-idin-1-yl)phenyl)ethan-1-one and heterocyclic aldehydes in methanol. The structures of the synthesized compounds were determined using data from various spectroscopic methods (IR,1H-NMR,13C-NMR, and LCMSMS). The compounds (50 mg/kg) were tested for their antidepressant-like effects by tail suspension and modified forced swimming tests (MFST). In addition, possible alterations in the locomotor activities of mice were evaluated by activity cage measurements. Obtained results showed that compounds 2c -2f reduced the immobility time of mice in both of the antidepressant activity-screening tests indicating that these derivatives have antidepressant-like effects. Moreover, in MFST, compounds 2c and 2e significantly increased the swimming times, while compounds 2d and 2f significantly prolonged the climbing dura-tions. Antidepressant-like effects of the compounds 2c and 2e were reversed withp-chlorophenylalanine methyl ester (serotonin depleting agent) pre-treatments while the same effect caused by the compounds 2d and 2f was abolished by pretreatment with alpha-methyl-para-tyrosine methyl ester (catecholamine deplet-ing agent) pre-administrations. Moreover, pre-treatment with naloxone reversed the antidepressant-like effects of these four derivatives. Obtained results indicated that monoaminergic and opioidergic systems mediated the antidepressant-like effects of our novel piperidine derivatives.