Present research work was undertaken to assess the effect of increased chain length of acyl group on the antidepressant activity of previously reported 2-(5H-[1,2,4]triazino[5,6-b]indol-3- ylthio)-N-(substituted phenyl)acetamides. Accordingly, various derivatives of 3-(5H- [1,2,4]triazino[5,6-b]indol-3-ylthio)-N-(substituted phenyl)propionamides C1–C18 were synthesized by reacting 1,2,4-triazino[5,6-b]indole-3-thione with 3-chloro-N-(substituted phenyl)propionamides and were characterized by IR, 1H NMR, 13C NMR, 13C DEPT, MS and elemental analysis. Synthesized compounds were evaluated for potential antidepressant activity by tail suspension test (TST). All the compounds exhibited moderate to weak antidepressant activity in comparison with standard drugs. Results of this study indicate that antidepressant activity of 2-(5H-[1,2,4]triazino[5,6-b]indol-3-ylthio)-N-(substituted phenyl)acetamides is severely mitigated on increasing chain length of its acyl group by one carbon.