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Abstract Sickle cell disease (SCD) is a life-threatening inherited hemoglobinopathy caused by a point mutation in the β-globin gene that results in hemoglobin S polymerization, red blood cell (RBC) sickling, vaso-occlusion, and hemolytic anemia. Globally, SCD affects over 300,000 newborns each year, with the highest prevalence in sub-Saharan Africa, India, and the Middle East. Childhood mortality exceeds 50% without proper care, and even in high-resource countries, life expectancy remains 20–30 years shorter than in the general population. Hydroxyurea (HU), a once-daily oral fetal hemoglobin (HbF) inducer and current standard-of-care, exerts its therapeutic effect by achieving sufficient HbF induction to prevent RBC sickling and hemolysis. However, its clinical use is limited by variable response, myelosuppression, gastrointestinal toxicity, and perceived carcinogenic risk. Curative approaches such as gene therapy have emerged, but their clinical application is limited by high cost, complex infrastructure, and long-term safety concerns. Gene editing therapies targeting BCL11A, as well as small-molecule degraders targeting the BCL11A repressor complex, represent next-generation HbF inducers aiming to provide more precise, durable, and potentially convenient therapy; however, their overall therapeutic impact is primarily HbF-dependent. Therefore, there remains a critical need for safe, effective, and convenient therapies that correct the underlying hematologic defects in SCD without totally depending on HbF induction. AND017 is a first-in-class oral hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) that elevates quantity and quality of RBC and hemoglobin levels. It has demonstrated safety and efficacy in preclinical anemia models and in phase 1 and 2 clinical trials in over 300 patients with chronic kidney disease anemia. To assess its therapeutic potential as a quantitative and qualitative RBC and hemoglobin-elevating therapy for SCD, we evaluated AND017 in the Townes SCD mouse model, which faithfully recapitulates key hematologic and pathophysiologic features of the human disease. Mice received oral administration of meglumine vehicle or 30 mg/kg AND017 in the same vehicle three times per week for over a year, starting shortly after hematologic abnormalities appeared. In vehicle-treated SCD mice, classic disease manifestations emerged by 5-8 weeks of age, to include reduced RBC count, hemoglobin concentration, and hematocrit, along with elevated white blood cell counts, mean corpuscular volume, and mean corpuscular hemoglobin. Notably, AND017 treated mice produced a marked hematologic recovery within 2 weeks of initiation. Complete blood count analyses revealed increases in RBC number, hemoglobin, and hematocrit, accompanied by reduction of RBC sickling, normalization of platelets and reduction of leukocytosis. Mitochondrial analysis during erythrocyte maturation demonstrated that AND017 enhanced reticulocyte maturation through increased mitophagy, resulting in the production of enucleated, mitochondria-depleted mature RBCs. The RBC lifespan in vehicle-treated SCD mice was only about one week. AND017 treatment significantly extended the lifespan to approximately two weeks, although it remained shorter than that of wild-type mice. This extension correlated with improved hematologic parameters and overall survival. Furthermore, to elucidate the mechanism by which AND017 improves SCD, we performed RNA-seq to characterize changes in gene expression induced by AND017 treatment. This analysis revealed that BNIP3, a well-characterized HIF1α target and mitophagy receptor, was upregulated following AND017 treatment compared with vehicle controls. In conclusion, our findings indicate that AND017 promotes terminal erythroid differentiation, thereby mitigating anemia and prolonging RBC survival in the Townes SCD model. Furthermore, AND017 functions as a HIF-PHI, promoting mitophagy and shifting mitochondrial metabolism toward glycolysis, which collectively promotes erythroid maturation and reduces the Mito-ROS and oxidative stresses in RBCs. Overall, our results support the potential of AND017 as a safe, efficacious, and orally convenient therapy for patients with SCD, warranting further clinical investigation.