Sickle cell anemia (SCA) is an inherited hematological disorder caused by the polymerization of defective hemoglobin that results in chronic hemolysis and recurrent vaso-occlusive crises. Conventional therapies, such as hydroxyurea administration and blood transfusions, have primarily focused on symptom management and offer only partial clinical benefits. Clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9) technology has introduced a paradigm shift in the treatment of SCA by enabling precise and potentially curative genetic modification. This review outlines the molecular pathophysiology of SCA and elucidates the mechanisms of CRISPR-related genome modifications, highlighting the therapeutic use of correcting the causative rs334 mutation and modulating BCL11A expression. Recent advancements in preclinical and clinical research have been discussed, along with ethical, regulatory, and translational considerations. Targeting the genetic etiology of SCA through CRISPR-Cas9 offers a promising route towards a permanent cure, underscoring its potential as a transformative strategy in the field of precision genomic medicine.