The β-hemoglobinopathies, including sickle cell disease (SCD) and β-thalassemia, are caused by mutations in the β-globin gene ( HBB) and affect millions of people worldwide. A curative strategy for the β-hemoglobinopathies would be ex vivo gene correction in patient-derived hematopoietic stem cells (HSCs) followed by autologous transplantation. Here we report the first CRISPR/Cas9 gene-editing platform for achieving homologous recombination (HR) at the HBB gene in HSCs by combining Cas9 ribonucleoproteins and rAAV6 HR donor delivery. Notably, we devise an enrichment paradigm to purify a population of HSPCs with >90% targeted integration. We also show efficient correction of the SCD-causing E6V mutation in patient-derived HSPCs that after differentiation into erythrocytes, express adult β-globin (HbA) mRNA, confirming intact transcriptional regulation of edited HBB alleles. Collectively, these preclinical studies outline a CRISPR-based methodology for targeting HSCs by HR at the HBB locus to advance the development of next generation therapies for β-hemoglobinopathies.