Abstract: OBJECTIVE To investigate the reverse effect of Acorus and Curcuma Decoction on despair like behavior in mice induced by hypercortisolism. METHODS 60 C57BL/6N mice were randomly divided into 6 groups: normal control， model control， Fluoxetine hydrochloride group， Acorus and Curcuma Decoction groups of high dose， middle dose and low dose. The hypercortisolism mice models were developed by subcutaneous corticosterone injection. Four weeks later， the changes of mice body， spleen and thymus mice weight were detected. After the forced swimming test and the tail suspension test finished， the mice were sacrificed by decapitation and the hippocampal tissues were rapidly collected for Western blot analysis of neurofilament light chain protein(NF-L) and synaptic vesicle protein(SYP). RESULTS Compared with the normal control group， the body weight was lower than model control group(P<0.05)， the immobility time was significantly prolonged in the forced swimming test and the tail suspension test (P<0.01)， spleen and thymus weight significantly decreased (P<0.05)， the expression of NF-L and SYP， were down-regulated in model control group(P<0.01). However， Acorus and Curcuma Decoction group， significantly shortened immobility time in behavioral science(P<0.01)， and up-regulated the expression of NF-L and SYP (P<0.01). CONCLUSION Acorus and Curcuma Decoction can protect neurons and antagonized the despair like behavior induced by hypercortisolism.