Abstract New technologies of induced pluripotent stem cells (iPSCs) and genome editing have emerged, allowing for the development of autologous transfusion therapies. We previously demonstrated definitive β-globin production from human embryonic stem cell (hESC)-derived erythroid cell generation via hemangioblast-like ES-sacs. In this study, we demonstrated normal β-globin protein production from biallelic corrected sickle cell disease (SCD) iPSCs. We optimized our ES/iPS-sac method for feeder cell-free hESC maintenance followed by serum-free ES-sac generation, which is preferred for electroporation-based genome editing. Surprisingly, the optimized protocol improved yields of ES-sacs (25.9-fold), hematopoietic-like spherical cells (14.8-fold), and erythroid cells (5.8-fold), compared with our standard ES-sac generation. We performed viral vector-free gene correction in SCD iPSCs, resulting in one clone with monoallelic and one clone with biallelic correction, and using this serum-free iPS-sac culture, corrected iPSC-generated erythroid cells with normal β-globin, confirmed at DNA and protein levels. Our serum-free ES/iPS-sac protocol with gene correction will be useful to develop regenerative transfusion therapies for SCD. Significance statement The sickle mutation in induced pluripotent stem cells (iPSCs) derived from a patient with sickle cell disease has successfully been corrected using an improved serum-free method for the generation of ES/iPS-sacs, a hemangioblast-like structure containing hematopoietic stem and progenitor cells that can be differentiated into erythroid cells containing mostly definitive globins, including γ- and β-globins.