Increased number of population with heart stroke/attack is attributed to sedentary lifestyle and consumption of high-sugar diets, especially fructose. The objective of this study is to investigate the cardio-protective activity of aqueous extract of Phyllanthus amarus (PAAE) against high-fructose (HF) diet induced cardiac damage in Wistar rats. Male Wistar rats were randomly assigned into five groups of six animals each: Control (C), Control treated with PAAE (C+PAAE), High fructose diet fed (F), High fructose diet fed treated with PAAE (F+PAAE) and High fructose diet fed treated with Pioglitazone (F+Pio). PAAE was orally administered at a dosage of 200mg/kg body weight/day to C+PAAE and F+PAAE group rats for 60days. Pioglitazone (10mg/kg body weight/day) was used to compare the efficacy of PAAE. After 60days, heart and aorta samples were collected for biochemical and histological analysis. Co-administration of PAAE along with HF-diet for 60days prevented the increase in levels of cardiac and aortic lipids i.e., total lipids, triglycerides, total cholesterol and free fatty acids and decreased phospholipids. Further, enhanced activities of cardiac aldose reductase (15.3%) and sorbital dehydrogenase (6.9%) and decreased activity of creatine kinase (35.6%) in group-F were also prevented by PAAE treatment with the recovery of 126% for AR, 122% for SDH and 118% for CK. PAAE treatment showed protection from HF-diet induced increase in stress markers (LPO and PO), decreased non-enzymatic (GSH and Vit-C) and enzymatic (GR, GPx, GST, SOD, and CAT) antioxidants in the heart and aorta. Histopathological examination of the heart and aorta indicated that PAAE/Pio treatment reduced fat deposition and necrosis. The present study clearly indicates the cardio protection efficacy of PAAE against HF-diet induced oxidative stress in rats.