Objective: To observe the effects of nootkatone on depression-like behavior, neurogenesis and protein kinase A(PKA)/cyclic adenosine monophosphate response element-binding protein(CREB)/brain-derived neurotrophic factor(BDNF) signaling pathway in hippocampus of chronic unpredictable stress(CUS) treated mice, and to explore the role and molecular mechanism of nootkatone′s antidepressant effect. Methods: Male C57 BL/6 mice were randomly divided into 3 groups: the control group(saline), the CUS group(CUS+saline), the CUS+nootkatone group(CUS+nootkatone). The sucrose preference test and forced swim test were used to evaluate the depression-like behaviors. The mRNA expression of BDNF in hippocampus was measured by RTPCR. The expression levels of BDNF, PKA and phosphorylated cyclic adenosine monophosphate response element-binding protein(p-CREB) in hippocampus were determined by Western blot. The level of neurogenesis was measured by immunofluorescence. Results: Compared with the control group, the sucrose preference decreased(P<0.05) and the latency decreased(P<0.05), and immobility time increased in forced swim test(P<0.05) in CUS group, the expression levels of BDNF mRNA(P<0.05) and protein(P<0.05), PKA(P<0.05) and p-CREB(P<0.05) decreased. The sucrose preference of the CUS+nootkatone group increased(P<0.05) and the latency increased(P<0.05), and immobility time decreased in forced swim test(P<0.05), the expression levels of BDNF mRNA(P<0.05) and protein(P<0.05), PKA(P<0.05) and p-CREB(P<0.05) increased in comparison with the CUS group. Compared with control group, the number of hippocampal doublecortin(DCX) labeled neurons decreased(P<0.05) in CUS group. Compared with the CUS group, the number of DCX labeled neurons increased in the CUS+nootkatone group(P<0.05). Conclusion The improvement of depressive symptoms in CUS mice by nootkatone may be related to the neurogenesis in dentate gyrus of hippocampus and the activation of PKA/CREB/BDNF signaling pathway.