This work proposed the cardioprotective mechanisms of Zingiber officinale (Ginger) rhizome and Moringa oleifera's leaf and seed methanolic extracts against doxorubicin (DOX)-mediated cardiotoxicity. Mice were distributed into groups: CNT group (normal control); DOX group (cardiotoxic control, 15 mg/kg BW); D+G, D+ML, and D+MS groups (pre-cotreated, 200 mg/kg BW); and G, ML, and MS groups (extracts' controls). The extracts' phytochemicals and antiradical activities were studied. Expression levels of cardiac nuclear factor (erythroid-derived 2)-like 2 (Nrf2), carbonyl reductase 1 (CBR1), and tumor necrosis factor-alpha (TNF-α), and oxidative stress were assessed. Serum lipids, cardiac enzymes, and cardiac histopathology were evaluated. The results showed that the extracts contain different phytochemicals and radicals scavenging abilities. DOX significantly increased the cardiac enzymes and induced cardiac redox disturbance and increased lipids as compared with the CNT group. Additionally, DOX significantly decreased the Nrf2 and CBR1 expression levels, but it significantly increased the TNF-α expression level. Conversely, the pre-cotreatments significantly prevented the DOX effects. Where, the expression levels of the tested genes, redox status, enzymes' activities, lipids, and histopathological changes were recovered. In conclusion, the extracts' cardioprotective potentials may be due to their modulation effects on the important regulator of the cellular redox homeostasis (Nrf2-CBR1), inflammatory cytokine (TNF-α), serum lipids, and their direct antioxidant activities.