Globally, cardiovascular diseases are becoming the major cause of death. Crassocephalum rubens is an indigenous vegetable used traditionally in the treatment of several disease conditions including stomach upset, wounds, and high blood pressure. However, there are limited literature reports on its hypolipidemic and cardioprotective activities, hence this study investigated the effects of leaf methanol extract and fractions of C. rubens on lipid profile, liver, cardiac marker enzymes; alanine (ALT), and aspartate (AST) aminotransferases, and cardiac tissue integrity in Isoproterenol-induced myocardial infarction (MI) in rats. Forty-five male Wistar rats were randomly divided into nine groups and administered different doses (100 & 150 mg/kg) of the plant extract and fractions for 14 days while normal control and MI control received phosphate buffer saline. C. rubens leaf methanol extract and fractions significantly (p<0.05) reduced TC (75.45 ± 2.44 - 96.09 ± 1.65 mg/dL), TG (84.04 ± 1.79 - 127.00 ± 0.47 mg/dL), VLDL-C (16.81 ± 0.36 - 25.42 ± 0.10 mg/dL), LDL-Cholesterol (03.49 ± 1.03 - 26.04 ± 1.64 mg/dL), and AST of the pretreated myocardial infarcted rats versus MI control (168.70 ± 9.85 mg/dL, 146.60 ± 1.74 mg/dL, 29.31 ± 0.34 mg/dL, 77.73 ± 9.67 mg/dL, respectively), while plasma HDL-C was increased. The crude extract and fractions of C. rubens showed significant cardioprotective activities on the integrity of the heart tissues of the experimental rats. The findings reveal antihyperlipidemic and cardioprotective potentials and provide a possible lead for isolation of bioactive compounds from C. rubens in the management of hyperlipidemia and its associated ailments.