Aim To investigate the effect of modified Zhishi Xiebai Guizhi decoction (Zhishi, Xiebai, Sanqi, Renshen, etc.) on the expression of aquaporin (AQP) in myocardial tissue of ischemia-reperfusion rats and its possible mechanism. Methods 52 SD rats were randomly divided into 4 groups:sham operation group (n＝10), model group (n＝14), Zhishi Xiebai Guizhi decoction group (ZXGD group, n＝14) and modified Zhishi Xiebai Guizhi decoction group (mZXGD group, n＝14). Left anterior descending coronary artery was ligated after 14 days of intragastric administration, and the myocardial ischemia-reperfusion injury model was established according to the method of ischemia 30 minutes and reperfusion 120 minutes. Changes of serum lactate dehydrogenase (LDH) and cardiac troponin I (cTnI) were detected by automatic biochemical analyzer. Change of cardiac histopathology was observed by HE staining. The levels of plasma adenylate cyclase (AC) and cyclic adenosine monophosphate (cAMP) were detected by enzyme-linked immunosorbent assay. Immunohistochemical staining was used to detect the positioning expressions of AQP1 and AQP4 in myocardial tissue.AQP1 and AQP4 mRNA expressions in myocardial tissue was detected by real-time fluorescence quantitative PCR. Western blot was used to detect protein expressions of protein kinase A (PKA), phosphorylated PKA (P-PKA), cAMP-response element binding protein (CREB), phosphorylated CREB (P-CREB), AQP1 and AQP4 in myocardial tissue. Results Compared with sham operation group, the contents of serum LDH, cTnI and plasma AC, cAMP were increased (P＜0.01), and the expressions of P-PKA, P-CREB, AQP1, AQP4 mRNAs and proteins in myocardial tissue were increased (P＜0.01), in model group. Compared with model group, the contents of serum LDH, cTnI and plasma AC, cAMP were decreased (P＜0.01), and the expressions of P-PKA, AQP1, AQP4 mRNAs and proteins in myocardial tissue were decreased (P＜0.01), in ZXGD group and mZXGD group. Compared with ZXGD group, the contents of serum LDH, cTnI and plasma AC, cAMP were decreased (P＜0.01), and the expressions of P-PKA, AQP1, AQP4 mRNAs and proteins in myocardial tissue were decreased (P＜0.01), in mZXGD group. Conclusion Modified Zhishi Xiebai Guizhi decoction can improve the pathological damage of myocardial cells after ischemia-reperfusion, and its mechanism may be related to down-regulating the AC/cAMP pathway and inhibiting AQP1, AQP4 mRNAs and proteins expression.