Cardiovascular disease (CVD) and its complications have been regarded as the leading cause of morbidity and mortality. The drugs available in the market are effective to treat CVD, but with many adverse reactions. Nowadays, herbal products are the attention of researchers because of their less adverse effects. In this study, the cardioprotective effects of ethanolic leaves extract of Psidium guajava Linn. (Guava) (P. guajava) were evaluated in streptozotocin (STZ)-treated animal models. Mice acquired for the study were divided into five groups, each consisting of six mice. The toxin-induced mice were treated with the ethanolic leaves extract of P. guajava (300 mg/kg body weight [b.w.]). The results were compared to the standard drug (glibenclamide)-treated mice (3 mg/kg b.w.). The following parameters were considered for further investigations: creatine kinase-muscle brain (CK-MB), creatine kinase (CK), troponin, lysosomal, and mitochondrial enzymes. Then the docking study was accomplished. The levels of cardiac marker enzymes and lysosomal enzymes increased significantly in the toxin-induced mice, while the level of mitochondrial enzyme decreased significantly. During treatment with the ethanolic leaves extract of P. guajava, the levels of all parameters were notably reversed to normal range (P < 0.05). Further, in docking analysis, the interaction of compounds, such as alpha-terpineol, cyclopentanecarboxamide, guaiol (a sesquiterpenoid alcohol), 1H-cyclopropanaphthalene, tetracyclotridecan-9-ol, dormin/abscisic acid, and epiglobulol, with the respective protein molecules, evidenced the cardioprotective effect of P. guajava leaves. Hence, it was concluded that the ethanolic leaves extract of P. guajava leaves have a cardioprotective effect.