To investigate the cardioprotective mechanism of Huangqi injection combined with puerarin injection on KKAy mice with diabetic cardiomyopathy, providing experimental evidence for the treatment of diabetic cardiomyopathy using traditional Chinese medicine. Methods KKAy mice were randomly divided into model group and treatment group (Huangqi injection combined with puerarin injection) according to blood glucose. The male C57BL/6J mice with same age were used as normal control group. The mice were sacrificed at 20, 24 and 28 weeks old, respectively. qRT-PCR was used for detecting the mRNA expression of IRE1α, XBP1U and XBP1S and Western blotting was used for assaying the expression of IRE1α and XBP1. Results:The mRNA and protein expression of IRE1α in the model group increased at 20, 24 and 28 weeks, while the increase of mRNA and protein expression of IRE1α reduced in the treatment group at 20, 24 and 28 weeks. The difference was statistically significant (P<0.05). The mRNA and protein expression of XBP1S at 20, 24 and 28 weeks and the mRNA expression of XBP1U at 28 weeks was increased in the model group; For the treatment group, the mRNA expression of XBP1S at 20 and 40 weeks and protein expression of XBP1 was down-regulated, whereas the expression of XBP1S and XBP1U mRNA increased. The difference was statistically significant (P<0.05). Conclusion:Huangqi injection combined with puerarin injection could inhibit the expression of IRE1α and XBP1, two stress signaling molecules of endoplasmic reticulum in the heart tissue of KKAy mice, and reduce the endoplasmic reticulum stress and exert cardioprotective effect on KKAy mice with type 2 diabetes.