Defects in cardiac contractility and heart failure (HF) are common following doxorubicin (DOX) administration. Different miRs play role in HF and their targeting was suggested as a promising therapy. We aimed to target miR-24, a suppressor upstream of junctophilin-2 (JP-2), which is required to affix sarcoplasmic-reticulum to T-tubules and hence the release of Ca2+ in excitation-contraction coupling using pachymic acid (PA) and/or losartan (LN). HF was induced with DOX (3.5mg/kg, i.p six-doses, twice weekly) in 24 rats. PA and LN (10mg/kg, daily) were given orally for four-weeks starting the next day of last DOX dose. Echocardiography, left ventricle (LV) biochemical and histological assessment and electron-microscopy were conducted. DOX increased serum BNP, HW/TL, HW/BW, mitochondrial number/size and LV expression of miR-24, while decreased EF, cardiomyocyte fiber diameter, LV content of JP-2 and rayanodine receptors-2 (RyR2). Treatment with either PA or LN reversed these changes. Combined PA+LN attained better results than monotherapies. In conclusion, HF progression following DOX administration can be prevented or even delayed by targeting miR-24 and its downstream JP-2. Our results therefore suggested a possibility of using PA alone or as an adjuvant therapy with LN to attain better management of HF patients specially those develop tolerance towards LN.