The current work is aimed at exploring the cardioprotective effect of ellagic acid (EA) and resveratrol (RES) against methotrexate (MTX), which causes cardiotoxicity. Rats were allocated into five groups as follows: Control, MTX group, EA protective group (30 mg EA/kg b.w.), RES protective group (25 mg RES/kg b.w.), EA plus RES group for 4 weeks. On the 22nd day of EA and RES administration, all groups were injected with MTX (20 mg kg bw i.p.). 4 weeks later, serum and cardiac tissues were collected for cardiac biomarkers, lipid profile and CRP measurement, cardiac histopathological picture, and immunoexpressing of cardiac IL-6 and IL-1β. MTX-induced cardiotoxicity, as confirmed through causing histopathological abnormalities of cardiac tissue, decreases cardiac GSH content and SOD activity in addition to significant elevation in cardiac biomarkers Treponin I, CKMB, and LDH beside cardiac inflammatory cytokines IL-6, IL-1β, and CRP. Similarly, MTX significantly increased serum AST, ALT activities, creatinine, and urea levels. On the contrary, oral supplementation of EA or/and RES attenuated alterations in the above-mentioned biomarkers and cardiac histopathological changes. The present results summarized that EA and RES treatment showed cardioprotective effects against MTX toxicity. Combining EA and RES gives the best result, as both increase total antioxidant capacity, protecting cardiac tissue from MTX toxicity.