The transcription factor Nrf2 (NF-E2-related factor 2) plays a critical role in oxidative stress responses. While activation of Nrf2 signaling is known to exert anti-inflammatory effects, Nrf2 function in inflammation-mediated autoimmune disorders, such as type 1 diabetes, is not well established. To address the roles of Nrf2 in protection against autoreactive T-cell-induced type 1 diabetes, we used non-obese diabetic (NOD) mice, a polygenic model of human type 1 diabetes, to generate a genetic model that allowed us to assess the contribution of Nrf2 activation to preventing and/or treating type 1 diabetes. As Keap1 negatively regulates Nrf2, we used Keap1 gene knockdown driven by either hypomorphic or knockout alleles of Keap1,which enhances Nrf2 signaling to moderate and excess levels, respectively. We found that Nrf2 activation in NOD::Keap1FA/- mice inhibited T-cell infiltration within or near the islets, ameliorated impairment of insulin secretion, and prevented development of diabetes mellitus in the NOD mice. Notably, Nrf2 activation decreased both plasma interferon-γ (IFN-γ) levels and IFN-γ-positive cell numbers in the pancreatic islets. These findings were also observed in mice with two hypomorphic Keap1 alleles (Keap1FA/FA). Both NOD::Keap1FA/- and NOD::Keap1FA/FA mice had decreased incidence of diabetes mellitus, demonstrating that the activation of Nrf2 signaling prevents the onset of type 1 diabetes mellitus in NOD mice. Thus, Nrf2 appears to be a potential target for preventing and treating type 1 diabetes.