This study explored the protective potential of NADPH-oxidase inhibitors, apocynin and curcumin in diclofenac-induced cardiotoxicity via oxidative stress. A total of 80 male Wistar rats were used for the study. 80 rats were randomly divided into 8 groups of 10 rats each. Group 1(control) received distilled water while others received orally, per mg/kg body weight of treatments as follows: group 2(1000, apocynin, group 3(1000, curcumin), group 4(10, diclofenac), group 5(500, apocynin and 10, diclofenac), group 6(1000, apocynin and 10, diclofenac), group 7(500, curcumin and 10, diclofenac) and group 8(1000, curcumin and 10, diclofenac). The treatments were administered daily for 14 and 28 days. Administration of diclofenac significantly (p<0.05) elevated the activities of NAD(P)H oxidases type 2 and malondialdehyde while the activities of superoxide dismutase, catalase, glutathione peroxidase and glutathione level were significantly (p<0.05) decreased. There was no alteration in the activities of xanthine oxidase. However, pretreatment with 500 and 1000 mg/kg body weight of apocynin or curcumin attenuated all biochemical alterations induced by diclofenac in a dose dependent manner. Pretreatments with apocynin and curcumin inhibitors of NOX 2 was effective in ameliorating diclofenac-induced cardiotoxicity by alleviating the oxidative stress thus, highlighting the therapeutic potentials of apocynin and curcumin in the management of diclofenac-mediated cardiotoxicity.