Type 2 diabetes is a metabolic disorder that results in β-cell dysfunction and ultimate destruction, and leads to impaired glucose homeostasis. High rates of proliferation and differentiation of pancreatic β-cells occurs mostly during neonatal development. However, research shows these mechanisms remain intact as β-cell proliferation has been observed during pregnancy and obesity. We have shown that overexpression of the β-cell transcription factor Nkx6.1 is sufficient to induce β-cell proliferation. Exploration of the transcriptional targets of Nkx6.1 has identified histone deacetylase 1 (HDAC1) as a down-stream target of Nkx6.1. Here we demonstrate that HDAC1 overexpression is sufficient to induce β-cell proliferation, enhance β-cell survival upon exposure to apoptotic stimuli and maintains glucose stimulated insulin secretion (GSIS). Our data suggests overexpression of HDAC1 leads to p15/INK4b suppression, a cell cycle inhibitor, potentially explaining the mechanism behind these observed effects. These data demonstrate that HDAC1 overexpression is sufficient to induce β-cell proliferation and enhance cell survival while maintaining glucose stimulated insulin secretion.