Myocardial infarction (MI) is a major health problem associated with high morbidity and mortality. Recently, angiogenesis has emerged as a novel therapeutic approach against ischemic diseases including MI. Therefore, we aimed to investigate the potential angiogenic effects of vanillin (Van) both alone and in combination with pentoxifylline (PTX), and to examine the molecular mechanisms through which Van and PTX may ameliorate cardiac injury induced in rats including their effects on oxidative stress, inflammation and apoptosis which play a key role in MI pathogenesis. MI was induced in rats using isoproterenol (ISO) (150 mg kg-1, SC, twice at a 24 h interval). Then, rats were treated orally with Van (150 mg kg-1 day-1), PTX (50 mg kg-1 day-1) or Van + PTX combination. ISO-induced cardiac injury was characterized by cardiac hypertrophy, ST-segment elevation and elevated serum levels of troponin-I, creatine kinase-MB and lactate dehydrogenase. Cardiac levels of the antioxidant markers GSH and SOD and the antiapoptotic protein Bcl-2 were decreased. On the other hand, cardiac levels of the oxidative stress marker malonaldehyde, the inflammatory cytokines TNF-α, IL-6 and IL-1β, the proapoptotic protein Bax, and caspase-3 were increased. Moreover, the cardiac levels of p-Akt and HIF-1α and the mRNA expression levels of the angiogenic genes VEGF, FGF-2 and ANGPT-1 were increased. Treatment with either Van or PTX ameliorated ISO-induced changes and further upregulated Akt/HIF-1α/VEGF signaling. Furthermore, Van + PTX combination was more effective than monotherapy. These findings suggest a novel therapeutic potential of Van and PTX in ameliorating MI through enhancing cardiac angiogenesis and modulating oxidative stress, inflammation and apoptosis.