Background Cyclosporine-A (Cs-A), an immunosuppressant drug indicated for organ transplant patients has been associated with toxicities arising from activation of pathological signalling. Meanwhile Ginkgo biloba supplement (GBS) is an antioxidant-enhancing herbal product widely used for treating neurological and vascular dysfunctions. Objectives This study investigated the ameliorative effect of GBS on cyclosporine-A induced cardiotoxicity in Wistar rats. Methods The study included 20 Wistar rats (n = 5) and they were treated as follows: group 1 received distilled water (10 mL/kg), group 2 received Cs-A (25 mg/kg), group 3 received GBS (50 mg/kg) and group 4 received Cs-A (25 mg/kg) and GBS (50 mg/kg). All treatment were done intraperitoneal for 14 days and thereafter, animals were euthanised and heart tissues were harvested for biochemical assays as well as immunohistochemical studies. Blood was also collected for serum biochemical studies. Results Our results revealed that GBS reduces Cs-A induced increase of AST, ALT, ALP, LDH, and GGT levels in serum relative to Cs-A group. Also, increased oxido-nitrergic markers like MDA, NO, together with elevated concentrations of cholesterol, triglycerides, LDL, creatine kinase-MB, troponin-I, as well as pro-inflammatory cytokines (IL-6, and TNF-α) and heart weight index were reduced by GBS. The Cs-A induced suppression of low-density lipoprotein, antioxidant (GSH, SOD, CAT), Na-K ATPase activities and antiapoptotic element, Bcl-2 were increased by GBS. Additionally, signalling pathways including ERK1/2, and mTOR as well as ventricular thickness were significantly alleviated by GBS treatment. Conclusion The findings suggest that GBS ameliorated Cs-A-induced cardiotoxicity by activating mTOR/ERK1/2 signalling pathways.