Objectives: The major adverse effect of doxorubicin (DOX) in cancer treatment is cardiac toxicity. Murva is a controversial plant used in the Ayurvedic system, which consist of more than 12 medicinal plant roots found in different parts of India. Marsdenia tenacissima (MT) is an acceptable source in Murva, whereas Sansevieria roxburghiana (SR) Schult & Schult.f. ( S. zeylanica Roxb.) are also considered as Murva in West Bengal, India. The present study focused on the evaluation of the cardioprotective mechanism as well as the in vivo cardioprotective potential of methanol extracts of MT and SR on rats by using in silico methods. Materials and Methods: A total of 48 rats were divided into 8 groups with 6 in each group. DOX 20 mg/kg, intraperitoneally (i.p.) was administered to all rats on the 13th day, with the exception of group 1. Group 2 was the disease control, group 3 was the treated with the standard drug propronolol, and groups 4 to 5 were treated with two lower doses of methanol extract of MT (MEMT) and methanol extract of SR (MESR), whereas group 7 received higher dose combinations of both extracts for 14 continuous days. Blood and tissue antioxidant levels as well as cardiac enzymes were measured at the end of the study. Damage to cellular functional units was analyzed by histopathological study. Dresgenin from MT similarly lupeol from SR were taken as ligands for the target peroxisome proliferator activated receptors (PPARα) protein to find out the mechanism of action. High-performance thin layer chromatography (HPTLC) fingerprinting was performed to determine the number of phytoconstituents present in both extracts. Results: The combination that showed the most significant (p<0.001) effect on altered cardiac enzymes and antioxidant enzyme levels in both blood and tissues also corrected the extreme damage in cellular functional units. Dresgenin and lupeol showed binding scores of -8.2 (kcal/mol) and -9 (kcal/mol), respectively, with PPARα. HPTLC reports revealed that 17 and 12 peaks were found at 254 nm for dresgenin and lupeol, respectively. Conclusion: The study results concluded that the combination of MESR and MEMT and that of MESR and MEMT exerted cardioprotective activity via binding of dresgenin and lupeol to PPARα. The order of efficacy was the extract combination > MESR > MEMT.