Background: Doxorubicin (DOX) is a potent chemotherapeutic drug that was widely used for treatment of various types of cancer. It produces free radicals which result in extreme dose-limiting cardiotoxicity. Objective: the present study was aimed to investigate the potential cardioprotective effect of exogenous NADPH, against doxorubicin-induced cardiotoxicity in albino rats. Material and Methods: thirty six adult albino rats (180–200 g) were divided into five groups which consist of negative control (group I), positive solvent control (group II), which subdivided into Subgroup IIa (saline): they received normal saline (0.9% NaCl) (solvent of Doxorubicin), and Subgroup IIb (modified saline): they received modified saline with PH:8 (normal saline +10% NaOH) (solvent of exogenous NADPH) Group III (exogenous NADPH): it was given in a dose (8 mg/kg/day) it was given iv/day for 7 days Group IV (Doxorubicin): rats received Doxorubicin in a dose (25 mg/kg), it was given (single dose); i.p. on the 7th day. Group V (Doxorubicin + exogenous NADPH): rats of this group received combination of Doxorubicin which was given in a dose (25 mg/kg) (single dose) i.p. on the 7th day and exogenous NADPH which was given in a dose (8mg/kg/day); iv/day for 7 days. Results: ECG analysis was done before and after treatment. On the 8th day, besides ECG analysis, cTnI, CK-MB, LDH, IL1 β, TNF α, Caspase-3, MDA and GSH were analyzed. Also, histopathological evaluation of isolated hearts was performed by light microscopy. DOX had significantly altered ECG, cTnI, CK-MB, LDH, IL1β, TNFα , Caspase-3, MDA and GSH Pre-treatment with NADPH significantly alleviated DOX-induced ECG changes and also guarded against DOX-induced rise of cTnI, CK-MB, LDH,IL1β, TNF α ,and Caspase-3 levels. NADPH also alleviated histopathological alteration in DOX-treated rats. Moreover, it significantly inhibited DOX-induced GSH depletion and elevation of MDA. Conclusion: It can be mentioned that exogenous NADPH alleviates the doxorubicin-induced cardiotoxicity. NADPH exerts these cardioprotective effects through different mechanisms of antioxidant, antiapoptotic, and anti-inflammatory effects.