Background: Cardiorenal crosstalk has gained growing scientific curiosity recently. Clinical observations have approved that heart and kidney performances are intimately interrelated; acute or chronic dysfunction of either is inevitably mirrored on the other. This coexistence usually has the poor prognosis and worsened outcome. Methods: We designed this study to explore therapeutic potentials of combined Vitis vinifera and Silymarin extracts on histopathological alterations of experimentally induced cardiorenal injury model. Moreover, to examine the pertinent role of Nrf2 in their bio-molecular actions. Sixty adult male Wistar albino rats were utilized, further subdivided into control, doxorubicin (DXR), DXR + Silymarin, DXR + Aqueous Vitis, DXR + Ethanolic Vitis, DXR + Ethanolic Vitis + Silymarin. Left ventricle and renal cortex sections from all groups were processed for histopathological examination, biochemical estimation of serum Urea, Creatinine, BUN, lipid profile and hsCRP and real-time PCR of Nrf2 expression in cardiac and renal tissue homogenate were performed. Results: Our results proved that combined ethanolic extract of Vitis vinifera and Silymarin restored normal renal and cardiac histomorphology. Significant improvement of Creatinine, BUN, lipid profile and hs-CRP cardiac and renal biochemical indicators confirmed our results. Moreover, significant elevation of mRNA expression levels of Nrf2 proved that combined Vitis vinifera and Silymarin action was directly related to the redox-sensitive regulator pathway. Conclusions: We concluded that synergistic therapeutic effect of Vitis vinifera extract and Silymarin on experimental cardiorenal injury model owes principally to promoting activation of the Keap1/Nrf2 signaling pathway.