<p>Sickle Cell Disease (SCD) is a common autosomal recessive hemoglobinopathy caused by a point mutation in the β-globin gene, leading to aberrant production of Hemoglobin S (HbS). The pathophysiological process initiated by this mutation triggers a cascade of symptoms, including erythrocyte sickling, vasococcus occlusions, chronic hemolysis, and widespread inflammatory reactions, culminating in a multitude of clinical complications. Unfortunately, in resource-poor regions, the increasing incidence of SCD outstrips the capabilities of public healthcare systems, thereby creating a dire and urgent requirement for readily available and optimized therapies. Hydroxyurea (HU) has proven itself as a definitive treatment that promotes fetal hemoglobin production, prevents clinical complications, and thereby provides a promising, cost-effective alternative to chronic blood transfusions. Recent findings indicate that microRNAs (miRNAs) play a pivotal role in regulating hematopoiesis and globin switching, thereby making them fundamental mediators and targets of HU therapy. In this review, we explore beyond the traditional frontiers of HU therapy by critically evaluating its rationale as a two-way modifier of the miRNA-scope, which affects crosstalk within a ceRNA network, promotes upregulation of desirable miRNAs, and also triggers HU-induced adaptive miRs that can potentially destabilize therapeutic responses or even induce adverse reactions. More importantly, this review proposes a new, comprehensive conceptual framework to overcome and explore the constraints of monotherapy. In a nimble review of prior findings, we clarify and establish which specific alterations of HU-induced miRs would form a rational basis and hypotensive stimulus of mimicking therapy and thereby differentiate which specific alterations of upregulated or downregulated miRs should form a systemic basis of antagomiring therapy and thus lay out a specific and comprehensive roadmap of combinatorial medicine and therapy in managing SCD.</p>