Background: Therapeutic strategies in cardiorenal syndrome (CRS) should be directed to the cardio-renal connectors like renalase. Coenzyme Q10 (CoQ10) and silymarin are natural anti-oxidant and anti-inflammatory agents. Objectives: Assessing the effect of CoQ10 and/or Silymarin on renalase gene expression in CRS induced by high fructose diet (HFD) in male rats. Patients and Methods: Fifty adult male albino rats of local strain were divided into 5 equal groups and subjected to the following regimens for 8 weeks: Group I: Supplemented orally with 1 ml of 2% aqueous solution of tween 80. Group II: Received HFD in the form of 30% fructose in drinking water. Group III: Received HFD and CoQ10 orally at a dose of 20 mg/kg/day dissolved in 2% tween-80 aqueous solution. Group IV: Received HFD and Silymarin orally at a dose of 200 mg/kg/day dissolved in 2% tween-80 aqueous solution. Group V: Received HFD and both CoQ10 and silymarin in the same regimen as described before. Results: CoQ10 and/or Silymarin significantly decreased plasma lipid profile, cardiac troponin-I, creatinine, malondialdehyde (MDA) & tumor necrosis factor alpha (TNF- α) levels when compared to HFD group. On the other hand, CoQ10 and/or silymarin caused significant increase in plasma catalase level & renalase gene expression in kidney tissue when compared to HFD group. They also improved HFD -induced cardiac and renal fibrosis. Conclusion: CoQ10 and Silymarin induced improvement in HFD-induced CRS as they possessed cardio-protective, reno-protective, hypo-lipidimic, anti-oxidant, anti-inflammatory and anti-fibrotic activities, as well as increased renalase expression.