Abstract: Hyperglycemia caused cardiac cell damage by increasing ROS production in diabetic complications. The current study will prove the antioxidant activity of Swietenia macrophylla (S. macrophylla) extract nanoparticles as a protector against Streptozotocin (STZ)-induced cardiac cell damage. In this research, high-energy ball milling is used to make S. macrophylla extract nanoparticle. Furthermore, characterize the size of S. macrophylla extract nanoparticles with Dynamic Light Scattering (DLS). Forty male rats were divided randomly into five groups. Control group: rats received orally aqua dest; Diabetic group: rats were injected STZ intraperitoneally; S. macrophylla group: rats were injected STZ and given orally with S. macrophylla extract nanoparticles. The DLS showed that the S. macrophylla extract nanoparticles size was 91.50 ± 23.06 nm. Injected with STZ significantly increased cardiac tissue of MDA levels, serum of CK-MB and LDH levels. STZ also significantly reduced expression of Nrf2, level of SOD and GPx in cardiac tissue compared with control group (p<0.05). In contrast, administration of S. macrophylla extract nanoparticles can prevent STZ-induced cardiac cell damage by decreasing level of CK-MB and LDH in serum, and level of MDA in cardiac tissue. S. macrophylla extract nanoparticles also significantly increments Nrf2 expression, SOD and GPx levels in cardiac tissue. These effects are related to the prevention of cardiac histopathological alteration (degeneration and necrosis) in diabetic rats. These results suggest that S. macrophylla nanoparticles might be a potential cardioprotective agent against STZ-induced cardiac cell damage due to its antioxidant properties