Background: Epigenetic modifications like promoter DNA methylation modulate the activity of cancer-associated genes. Pomegranate fruit extract (PE) possesses immense potential in cancer treatment. To the best of our knowledge, the effect of PE on DNA methylation status has not yet been investigated or reported before. Aim: to investigate the potential that PE exerts its anti-cancer effects by altering the expression of proapoptotic Caspase-3 and proangiogenic VEGF genes via modulating their promoter methylation status in breast cancer (BC) patients receiving chemotherapy. Material and Methods: Bioinformatics analysis followed by Methylation-specific PCR were used to assess the methylation of Caspase-3 and VEGF genes in 25 healthy females receiving 500 mg PE daily, 25 BC patients receiving a chemotherapy regimen (AC 60/600), and 31 BC patients receiving a combination of (AC 60/600) + 500 mg of PE. To investigate if methylation was the major effector on gene expression, protein levels for cleaved Caspase-3 and VEGF were measured by ELISA. Finally, since dietary antioxidants alter the pattern of DNA methylation, serum antioxidant power was measured using the FRAP assay. Results: PE dietary supplementation reduced the methylation of Caspase-3 in patients receiving Chemotherapy + PE (12% to 3%), and increased the caspase-3 protein level by 74.2%. On the other hand, combination treatment slightly enhanced the methylation of the VEGF promoter and reduced its protein level by 36.99%. Conclusion: This study is the first that reports the modulation of DNA methylation status as a novel anti-cancer epigenetic mechanism of action for PE by pro-apoptotic and anti-angiogenic effects.