Objective To study the mechanism by which sodium aescinate (SA) reduces the areas of myocardial infarction area and no-reflow through the p38MAPK pathway in rats. Methods Adult male Sprague-Dawley rats were randomly divided into seven groups as follows: control, ischemia-reperfusion ( I/ R), I/ R+SA, blank adenovirus+I/ R, p38MAPK adenovirus+I/ R, blank adenovirus+I/ R+SA, and p38MAPK adenovirus+I/ R+SA. The myocardial I/ R model was established by ligating the anterior descending branch of the left coronary artery. Intervention comprised intraperitoneal injection of SA or local injection of adenovirus. Staining was used for detection as follows: thioflavin S for myocardial no- reflow area, nitrotetrazolium chloride blue for myocardial infarction area, and terminal deoxynucleotidyl transferase dUTP nick end labeling for apoptosis. Enzyme-linked immunosorbent assay was used to detect interleukin ( IL-1β), tumor necrosis factor (TNF-α) and intercellular adhesion molecule (ICAM-1). Western blot was used to detect the expression of Bax, cleaved caspase-3 and phosphorylated p38 MAPK (p-p38 MAPK). Results Compared with the I/ R group, the areas of myocardial no reflow and infarct were significantly reduced, and there were significant decreases in the apoptosis rate, contents of IL-1β, TNF-α and ICAM-1, and the expression of Bax, cleaved caspase-3 and p-p38 MAPK (P<0. 05). Compared with the blank adenovirus+I/ R group, the areas of myocardial no reflow and infarct were significantly enlarged, and there were significant increases in the apoptosis rate, contents of IL-1β, TNF-α and ICAM-1, and the expression of Bax, cleaved caspase-3 and p-p38MAPK, in the p38MAPK adenovirus+I/ R group (P<0. 05). Compared with the blank adenovirus+I/ R+SA group, the areas of myocardial no reflow and infarct were significantly enlarged, and the apoptosis rate, contents of IL-1β, TNF-α and ICAM-1, as well as the expression of Bax, cleaved caspase-3 and p-p38MAPK, were significantly increased in the p38MAPK adenovirus+I/ R+SA group (P<0. 05). Conclusions SA reduced the myocardial infarction area and no-reflow area of rats after myocardial I/ R. The molecular mechanism for SA involves inhibition of the p38MAPK pathway to mediate the inflammatory response and apoptosis.