Sickle cell disease (SCD) remains one of the most significant monogenic disorders globally, with Nigeria bearing the highest prevalence, accounting for nearly 50% of the world’s annual births with SCD. The genetic landscape of SCD in Nigeria is remarkably heterogeneous, characterized by diverse β-globin haplotypes, varying allele frequencies, and multiple genetic modifiers influencing clinical outcomes. This review synthesizes current knowledge on the molecular and haplotypic diversity of SCD in Nigeria and highlights its implications for disease phenotype, prognosis, and therapeutic response. We critically evaluate the current management landscape, including hydroxyurea therapy, transfusion programs, and newborn screening efforts, while identifying barriers to equitable access. Furthermore, we examine emerging gene therapy approaches—lentiviral gene addition, CRISPR-Cas9 gene editing, and HbF reactivation—and assess their relevance to Nigeria’s unique genotype distribution and healthcare infrastructure. Finally, we discuss health equity, policy priorities, and capacity-building strategies necessary to ensure broad, affordable access to curative therapies. Our review underscores the dual imperative of scientific innovation and health equity to transform SCD outcomes in Nigeria.