Ischemic heart disease (IHD) is a severe cardiovascular condition characterized by impaired blood flow to the heart muscle, leading to tissue damage and dysfunction. Among different natural resource, mushrooms are now becoming more attractive because of its strong nutritional value and therapeutic potentiality. Wild edible fleshy fungi like Volvariella volvacea have been instrumental in preventing and treating chrome diseases. Hence, this study was carried out to evaluate the cardio-protective activity of Volvariella volvacea in isoproterenol-induced myocardial infarction using animal model. Twenty five (25) male wistar rats were randomly grouped into five classes (A, B, C, D and E) of five rats each. Groups A, B and C were pre-treated with 100mg/kg, 200mg/kg and 400mg/kg of Volvariella volvacea extract respectively. Group D was administered 10 mg of lisinopril (standard drug), this served as the positive control group while group E was administered 0.2 ml distilled water, and this served as the negative control group. All the rats were intraperitoneally induced with 150 mg of isoproterenol after fourteen days (two weeks) of pretreatment. Cardiac biomarker (lactate dehydrogenase (LDH)), was measured to assess cardiac injury, using standard method while lipid bioassay such as high density lipoprotein (HDL), low density lipoprotein (LDL), triglycerides (TG) and total cholesterol (TC) were assayed using standard assay kits. Results showed that rats pre-treated with Volvariella volvacea extract showed significant effect on cardiac biomarkers compared to the control group. Results showed a significant increase (P<0.05) in high density lipoproteins (HDL) levels and lactate dehydrogenase (LDH) activities with a significant decrease (P>0.05) in low density lipoproteins (LDL) and triglyceride levels in a dose-dependent manner (100<200<400 mg/kg body weight) among the extract treated groups when compared to the untreated control group. However, total cholesterol levels of extract treated groups showed no significant difference when compared with the untreated control group. This study has shown that extract of Volvariella volvacea could help to mitigate cardiovascular diseases and could be used to produce plant based products to combat Ischemic heart disease, and consequently improving general wellbeing.