Ischemic heart disease (IHD), a severe condition of myocardium facing impediment in the supply of basic needs for cellular metabolism is caused by atherosclerosis. Though statin drugs could control the use of surgery on IHD patients, the complete rehabilitation or prophylaxis can be achieved through herbal-based medicines viz. either in the form of crude extract or pure phytocompounds. In the present study, pretreatment with leaf extract of Nelumbo nucifera Gaertn. was investigated for cardioprotective activity—in vitro by mitigating H2O2-induced oxidative stress. Analysis such as estimation of antioxidants, lipid peroxidation, and DNA fragmentation assay revealed significant protective effect of plant extract on cardiomyocytes. Reactive oxygen species detection was done by using 2′,7′-dichlorofluorescein diacetate, apoptosis detection with Acridine Orange/Ethidium Bromide and nuclear damage detection by diamidino-2-phenylindole which confirmed the protective effect of N. nucifera extract. In addition, gene expression studies of apoptotic regulatory genes (Bcl2 and Cas-9) resulted in significant protection of nucifera extract pretreated and maintained cells. To conclude, in vitro cardioprotective activity of N. nucifera against H2O2 induced oxidative stress was achieved at the concentration of 50 µg/ml. Therefore, major phytocompounds present in extract could be beneficial in managing cardiac complications in the future. © 2019, Springer Nature B.V.