“Beta-thalassemia is a hereditary hemoglobinopathy caused by mutations in the HBB gene, which compromise the synthesis of the β-globin chain of hemoglobin, resulting in chronic anemia and transfusion dependence. Gene therapy based on CRISPR-Cas9 emerges as a promising alternative to correct these mutations, allowing both the direct restoration of β-globin expression and the therapeutic reactivation of fetal hemoglobin (HbF) through the modulation of regulatory elements such as BCL11A. This narrative and analytical literature review examines the main technological and clinical advances related to the use of the CRISPR-Cas9 system and its variants (Cas12a, base editing, and prime editing) in β-thalassemia, with emphasis on genomic safety, therapeutic efficiency, and implementation feasibility. Delivery methods such as RNP, AAV6, and lipid nanoparticles are discussed, in addition to in vivo editing strategies and the integration of artificial intelligence into gRNA design. Despite the progress achieved, challenges persist regarding off-target effects, p53 activation, clonal stability, and the high costs that limit applicability in public health systems, particularly in the Brazilian context. It is concluded that, although still in the translational phase, CRISPR-Cas9 represents one of the most revolutionary tools for the curative treatment of β-thalassemia, paving the way for safer, more precise, and more accessible therapies, in which the biomedical professional plays an essential role in technical validation, monitoring, and laboratory biosafety” (2025) Revista Multidisciplinar do Nordeste Mineiro, 20(2), pp. 1–27. doi:10.61164/ef6z6361.