Aim To investigate the effect and its mechanism of 8-O-acetyl-SM on acute myocardial infarction rats based on p38 MAPK-CRYAB pathway. Methods A rat model of acute myocardial infarction was established by ligation of the left anterior descending coronary artery. Fifty male SD rats were randomly divided into model control group, positive control group, 8-O-acetyl-SM low, medium and high dose groups, with 10 rats in each group. In addition, 10 rats were used as blank control groups. The blank control group and the model control group were given the same volume of normal saline, the positive control group was given aspirin enteric-coated tablets (100mg/(kg·d)), and the 8-O-acetyl-SM low, medium and high dose groups were given 0,0 and 30 mg/(kg·d) 8-O-acetyl-SM, continuous administration for 14 days. The changes of cardiac function were detected, HE staining was used to observe the pathological changes of myocardium in rats, TUNEL was used to detect the apoptosis of myocardial cells, ELISA was used to detect the levels of SOD, LDH, GSH-Px and MDA, RT-PCR was used to detect the mRNA expression of Bcl-2, Bax and Caspase-3, Western blot was used to detect the expression of p-p38 MAPK/p38 MAPK and p-CRYAB/CRYAB. Results 8-O-acetyl-SM significantly could improve cardiac function and pathological changes of myocardial tissue in rats with acute myocardial infarction (P＜0.05), reduce myocardial apoptosis rate (P＜0.05), reduce oxidative stress damage (P＜0.05), up-regulate the expression of Bcl-2, down-regulate the expression of Bax and Caspase-3 (P＜0.05), promote phosphorylation of p38 MAPK and CRYAB (P＜0.05), but there was no significant change in the expression of p38 MAPK and CRYAB protein among the groups (P＞0.05). Conclusion 8-O-acetyl-SM can significantly improve myocardial injury symptoms, up-regulate Bcl-2 expression, down-regulate Bax and Caspase-3 expression, promote p38 MAPK and CRYAB phosphorylation, and its mechanism may be related to p38 MAPK-CRYAB pathway.