Pancreatic β cell neogenesis and proliferation during the neonatal period are critical for the generation of sufficient pancreatic β cell mass/reserve and have a profound impact on long-term protection against type 2 diabetes (T2D). Oxidative stress plays an important role in β cell neogenesis, proliferation, and survival under both physiological and pathophysiological conditions. Pancreatic β cells are extremely susceptible to oxidative stress due to a high endogenous production of reactive oxygen species (ROS) and a low expression of antioxidative enzymes. In this review, we summarize studies describing the critical roles and the mechanisms of how oxidative stress impacts β cell neogenesis and proliferation. In addition, the effects of antioxidant supplements on reduction of oxidative stress and increase of β cell proliferation are discussed. Exploring the roles and the potential therapeutic effects of antioxidants in the process of β cell regeneration would provide novel perspectives to preserve and/or expand pancreatic β cell mass for the treatment of T2D.