Background: The limiting factor in the use of cyclophosphamide (CYP) in cancer chemotherapy is its induced oxidative cardiotoxicity. Objectives: This study aims to investigate the possible protective effect of caffeic acid phenethyl ester (CAPE) in the co-administration of CYP and naproxen (NAP) with acute and subchronic treatments in mice. Materials and Methods: Male BALB/c mice were divided into two phases of acute (24 h) and subchronic (30 days) treatments, of which seven groups each were used. Two groups from both acute and subchronic treatments represented untreated controls and CAPE groups, while others were CYP, NAP, CYP+NAP, CYP+CAPE and CYP+NAP+CAPE groups for both treatments. The activity of the cardiac antioxidative enzyme catalase was measured. The levels of cardiac reduced glutathione (GSH), protein carbonyl and malondialdehyde (MDA) were also assayed. In addition, histopathology of the heart tissues and immunohistochemistry of endothelial nitric oxide synthase (eNOS) expression were evaluated. Results: Our results showed that catalase and GSH were significantly decreased in all subchronic treatments. Furthermore, protein carbonyl and MDA were increased in both acute and subchronic treatments. Histopathological examination showed hypertrophic cells induced by CYP, NAP, and in combination. Moreover, CYP, NAP and in combination, significantly reduced eNOS levels. However, CAPE significantly prevented changes induced by CYP and NAP in both treatment groups. Conclusion: These observations highlight the protective potentials of CAPE in CYP-NAP-induced cardiotoxicity.