Objective . This study was aimed at observing the effect Jiao‐Tai‐Wan in menopausal depression. Methods . In this paper, we used ovariectomized mice subjected to chronic unpredictable stress as a menopausal depression model. After the chronic stress, mice were administrated with JTW (3.3 and 6.6mg/kg) and imipramine (10 mg/kg) for 14 days. On the 14th day, mice were subjected to the behavior test like the forced swim test, tail suspension test, and locomotor activity or were sacrificed to assess the protein changes in different brain regions. Results . The administration of JTW at doses of 3.3 and 6.6mg/kg (p.o.) significantly shortened the duration of immobility in forced swim and tail suspension tests. There was no obvious difference in locomotor activity among all the groups. The western blot analysis data indicated that treatment with JTW (3.3 and 6.6 mg/kg, p.o.) prominently increased the A 1 R protein and the downstream protein ERK1/2 levels in the prefrontal cortex and hippocampus. However, the administration of JTW did not influence c‐Fos protein in either the prefrontal cortex or hippocampus. Conclusion . Our findings suggest that JTW plays a vital role in ameliorating menopausal depression symptoms in the A 1 R‐ERK1/2 pathway in the prefrontal cortex and hippocampus.