Type 1 diabetes is characterized by the destruction of pancreatic β cells, and generating new insulin-producing cells from other cell types is a major aim of regenerative medicine. One promising approach is transdifferentiation of developmentally related pancreatic cell types, including glucagon-producing α cells. In a genetic model, loss of the master regulatory transcription factor Arx is sufficient to induce the conversion of α cells to functional β-like cells. Here, we identify artemisinins as small molecules that functionally repress Arx by causing its translocation to the cytoplasm. We show that the protein gephyrin is the mammalian target of these antimalarial drugs and that the mechanism of action of these molecules depends on the enhancement of GABAA receptor signaling. Our results in zebrafish, rodents, and primary human pancreatic islets identify gephyrin as a druggable target for the regeneration of pancreatic β cell mass from α cells. Display omitted •Artemisinins inhibit ARX function and impair α cell identity•Compounds act by stabilizing gephyrin, thus enhancing GABAA receptor signaling•Artemisinins increase β cell mass in zebrafish and rodent models•Functional and transcriptional data indicate a conserved phenotype in human islets The anti-malarial drug Artemisinin can drive the in vivo conversion of pancreatic α cells into functional β-like cells through enhanced GABA signaling and may have potential as a therapeutic for diabetes.