Sixteen 1,3-diynes compounds were designed and synthesized. Their protective effects on corticosterone-injured PC12 cells were evaluated. Among them, five compounds (7a, 7c, 7d, 11, 12) displayed significant protective activity at 10 μmol. Moreover, the protective activity of compound 7a was proved to be associated with the regulation of the apoptosis related proteins. The mice forced swim test showed that 7a had a concentration-dependent antidepressant-like effect. Overall, our findings support that compound 7a is a promising lead candidate that deserves further evaluation in the design of antidepressants.