The aim of this study is to explore the effect of Tinospora cordifolia (Guduchi) on cardiotoxicity in streptozotocin induced diabetic rats. All animals were divided into 8 groups of 5 animals each, fed with High fat diet (HFD) except the ones in Sham, NPD and NPD-C-I groups. Food and water intake were monitored daily at the same time during the experimental period. The Food Efficiency Ratio (FER) was calculated during the experiment period. All the animals were pretreated as per the treatment protocol. Streptozotocin; STZ (50mg/ Kg) was administered subcutaneously to induce the diabetes which was confirmed in all the administered groups by testing blood glucose level after 48 hours. Cardiotoxicity was induced by administering isoprenaline (85mg/Kg). Troponin was checked after 4-5 hours of second isoprenaline injection to confirm cardiac damage. At the end of the study the animals were weighed and then sacrificed with high dose of Diethyl ether. Blood samples were collected from retro-orbital plexus and were used for biochemical estimations. The hearts were excised immediately and were weighed. Photomicrographs were taken for gross examination rest of the hearts were kept in 10% Formalin solution for histopathological studies. Pretreatment with Tinospora cordifolia (200 mg/kg ) showed very significant improvement against Streptozotocin induced diabetes (p< 0.01) as blood glucose level were found to be decreased when compared to the untreated D-HFD group. The Food efficiency ratio (FER) was found to be significantly increased when compared to D-HFD (p<0.01). Significant decrease in the elevated activities of the cardiac marker enzymes, viz, alanine transaminase (ALT) (p < 0.01), lactate dehydrogenase (LDH) (p < 0.01), creatinine kinase (CK-MB) (p < 0.01) and negative troponin test were observed. The observed results were further confirmed by histopathological findings which indicated that Tinospora cordifolia (200mg/Kg) shows highly significant reduction in cardiotoxicity and considerable improvement, compactly arranged muscle fibres with minimum interstitial tissue, long spindle shaped vascular nuclei and well marked muscles striations.The findings of this study indicate that Tinospora cordifola (Guduchi) root extract exerts potent cardioprotection against isoprenaline induced cardiotoxicity in diabetic rats. This effect is comparable with that of carvedilol and pioglitazone.