Inhibition of histone deacetylase (HDAC) suppresses inflammation of pancreatic islets and apoptosis of β-cells. However, the underlying molecular mechanism is unclear. In the present study, we demonstrate that MGCD0103 (MGCD), an HDAC inhibitor, protects the pancreas from streptozotocin (STZ)-induced oxidative stress and cell death. Sprague-Dawley rats were intraperitoneally injected with STZ (40 mg/kg) to induce type I diabetes. MGCD (10 μg/day) was infused with osmotic mini-pump for 4 weeks. Pancreatic insulin and macrophage infiltration were analyzed by immunohistochemistry. Cellular level of reactive oxygen species (ROS) was evaluated with fluorescence-activated cell sorting. Tetramethylrhodamine ethyl ester was used to analyze mitochondrial membrane potential. Activation of caspase-3 was analyzed by western blotting. Chromatin immunoprecipitation was performed to investigate the binding affinity of specificity protein 1 (SP1) on the promoters of target genes. mRNA expression was analyzed by quantitative real-time polymerase chain reaction. As a result, we found that MGCD infusion ameliorated STZ-induced hyperglycemia, islet deformation, decreased insulin level, and macrophage infiltration. STZ injection promoted the production of ROS, which induced caspase activity and β-cell death. 4-Hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPOL), a mimetic of superoxide dismutase (SOD), reduced STZ-induced caspase activity and β-cell death. MGCD treatment increased SOD expression and histone acetylation level on promoters. Infusion of MGCD promoted acetylation of SP1 and its enrichment on SOD promoters. Thus, MGCD protects pancreatic β-cells from STZ-induced oxidative stress and cell death through the induction of antioxidant enzymes such as SODs.