Background: Myocardial infarction (MI) continues to be associated with high morbidity and mortality worldwide. Proton Pump inhibitors (PPIs) exhibit cardioprotective effects by several mechanisms. Vitamin E possesses antioxidant properties. Aim: The present study has been designed to evaluate the combined cardioprotective effect of PPIs and vitamin E on biochemical and histopathological alteration in isoprenaline (ISO) induced myocardial infarction in rats. Methods: 30 adult Wistar albino male rats divided into 5 groups as follow: Group I: Control fed a standard diet.Group II: rats were undergoing MI by ISO. Group III: Rats were pretreated pantoprazole (1.3 mg/kg, i.o) daily for 3 weeks. Group IV: Rats were pretreated with vitamin E (100 IU/kg i.o) daily for 3 weeks. Group V: Rats were given both pantoprazole (1.3 mg/kg, i.o) and vitamin E (100 IU/kg bw, i.p) daily. On 22^thand 23^th day, rats in groups (II-V) were injection i.p with ISO (100mg/kg bw for successive two days). Results: ISO induced infarction in rats resulted in a significant elevation in ST segment height, T – wave voltage, Heart rate (HR), serum lactate dehydrogenase (LDH), malondialdehyde (MDA) and nitric oxide metabolites (NO), whereas it caused a significant (P < 0.05) decrease in systolic blood pressure(SBP) and serum superoxide dismutase (SOD) when compared with the control group. Moreover, interventions with PPIs supplementation and/or vitamin E significantly reversed the aforementioned parameters with better impact of their combination. Conclusion: PPIs combined with vitamin E exert potential protective effect against MI through lowering calcium overload and enhancement of antioxidant activity.