Our study evaluates the effects of sacubitril/valsartan (SAC/VAL) in the rabbit model of doxorubicin-induced heart failure. Twenty rabbits (5 per group) were administered with doxorubicin (DOX, 1.5 mg kg–1, i.v.) to induce heart failure. Specific biomarkers such as BNP, CnT, CRP and ROMs were determined. The cardiac enzymatic antioxidant systems were recorded with their electrographic profiles. HR, SBP, DBP and MAP were restored at 5 or 10 mg kg–1 (p.o.) of SAC/VAL compared to DOX, followed by reduced levels of creatinine and BNP (p < 0.001). Significant improvements (p < 0.05) compared to DOX were also noticed in CAT, SOD and LPO with the same doses of SAC/VAL. Specific biomarkers such as BNP, CnT, CRP and ROMs descended significantly (p < 0.001) with treatment when compared to their baseline values. Our findings implied that SAC/VAL treatment reduced the inflammation and oxidative stress to improve the cardiac function.