A new series of coumarin based aminopyran derivatives were designed, synthesized and evaluated for their preclinical antidepressant effect on Swiss albino mice. Among the series, compounds 21, 25, 26, 27, 32 and 33 exhibited significant activity profile in forced swimming test (FST). Compound 27 was most efficacious, which at a very low dose of 0.5mg/kg reduced the time of immobility by 86.5% as compared to the standard drug fluoxetine (FXT) which reduced the immobility time by 69.8% at the dose of 20mg/kg, ip. In addition, all active compounds were screened in dose dependent manner (at doses of 0.25, 0.5, 1mg/kg ip) in FST and tail suspension test (TST). Interestingly, all active compounds did not caused any significant alteration of locomotor activity in mice as compared to control, indicating that the hybrids did not produce any motor impairment effects. The results indicate that coumarin-aminopyran derivatives may have potential therapeutic value for the management of mental depression.