Between 7 and 28% of patients receiving cyclophosphamide (CP) have cardiotoxicity. This study looked to learn more about the enhancement effects of Mangiferin on the therapeutic efficacy of bone marrow mesenchymal stem cells (BM-MSCs) on CP-induced cardiac toxicity in adult rat models. Ninety male albino rats were separated into six groups: control, CP, withdrawal, CP plus Mangiferin, CP plus BM-MSCs, and CP plus Mangiferin and BM-MSCs groups. When the cardiac muscle of the CP group was examined under a microscope, the cardiac muscle fibers were vacuolated, and there was mononuclear infiltration between the fibers. Also, myofibril disintegration, enlarged, dilated SER, and degenerated mitochondria were observed ultra-structurally. Some nuclei had chromatolysis, whereas others were heterochromatic with irregular nuclear membranes. These outcomes were validated by a highly significant increase in α-SMA and a highly significant decrease in Bcl-2, as well as increased collagen fiber deposition, additionally confirmed by biochemical results in the form of elevated serum levels of CK-MB and LDH and tissue MDA levels. The withdrawal group's outcomes resembled those of the CP group. The CP plus Mangiferin group and CP plus BM-MSCs groups improved cardiac muscle architecture, collagen fiber deposition, serum levels of CK-MB, LDH, and tissue MDA levels, but still did not achieve complete improvement in histological, ultrastructural, Immunohistochemical, and biochemical cardiac parameters. Lately, the CP plus Mangiferin and BM-MSCs group produced results closely similar to the control group.