Objective To investigate the antidepressant effect of DS-1226, a hydrolysate of ginsenosides, on a mouse model of depression induced by chronic sleep interruption, and provide scientific evidence for the research and development of antidepressant drugs. Methods 72 male ICR mice were divided into control group, model group, positive control group (paroxetine hydrochloride, 10 mg/kg) and 3 treatment groups (20 mg/kg, 40 mg/kg, 80 mg/kg of DS-1226). Except the control group, the other mice were put into a rotary roller (parameter settings:1 min/rev;rest 2 min after 1 rev) for 3 days of drum adaptation, 3 h/d. Then making model for 14 days in the roller(parameter settings:1 min/rev;rest 2 min after 1 rev). The antidepressant effects of DS-1226 were evaluated by weight monitoring, open-field test, tail suspension test, and forced swimming test. Results After 14 d sleep disturbance, compared with the control group, the body weight, immobility time in tail suspension test and forced swimming test were significantly decreased in the model group. Compared with the model group, DS-1226(40 mg/kg)significantly reversed the weight loss caused by sleep disturbance. Paroxetine significantly reduced the immobility time of tail suspension test. DS-1226 (40 mg/kg, 80 mg/kg)significantly decreased the immobility time of tail suspension test, and DS-1226 (80 mg/kg) significantly decreased the immobility time of forced swimming test. Conclusion The hydrolysate of ginsenosides DS-1226 shows antidepressant effect on mouse model of depression induced by chronic sleep interruption.