Background Recent studies have provided evidence that microRNAs (miRNAs), as a potential biomarker, were involved in the regulation of gene expression in Myocardial Infarction (MI). This study aimed to highlight the role of salvianolate on cardiomyocyte apoptosis in MI. Methods Anterior descending branch of left coronary artery was ligated to set up MI model. MiR- 122-5p mimic was transfected into cardiomyocytes and verified by quantitative real-time PCR (qRT-PCR). Cell viability and apoptotic rate were measured by MTT assay and flow cytometry together with TUNEL method, respectively. Changes in the expression of caspase-3, Bax and Bcl-2 were quantified by qRT-PCR and western blot. Results After treatment with salvianolate, miR-122-5p expression and caspases-3 activity significantly decreased in rat myocardial tissues. Furthermore, cardiomyocytes apoptosis rate was obviously suppressed while cell viability dramatically increased in H9C2 cardiomyocytes. However, overexpression of miR-122-5p reversed the aforementioned trends. Simultaneously, it could also mitigate the anti-apoptosis effect of salvianolate on the upregulation of caspases-3 viability and Bax expression and downregulation of Bcl-2 expression. Conclusion Salvianolate induces the anti-apoptosis mechanism of cardiomyocytes via downregulation of miR-122-5p, Bax expression and caspases-3 as well as upregulation of Bcl-2 expression. In contrast, overexpression of miR-122-5p inhibits the effect of salvianolate.