Sickle cell disease (SCD) is one of the most prevalent hemoglobinopathies worldwide, particularly in regions with high genetic predisposition. Early diagnosis through newborn screening (NBS) is critical for initiating interventions that significantly reduce morbidity and mortality. This systematic review evaluates the current methodologies used in NBS for SCD, comparing their sensitivity, specificity, and feasibility of implementation in different settings. We also explore recent innovations, including point-of-care (POC) tests and molecular diagnostics, that are transforming early detection strategies. Our findings suggest that while high-performance liquid chromatography (HPLC) and tandem mass spectrometry (MS/MS) remain gold-standard techniques, newer POC assays offer promising alternatives for resource-limited settings. The integration of artificial intelligence (AI) and genomic screening could further enhance diagnostic accuracy and accessibility. Future directions should focus on optimizing screening programs for global implementation and ensuring equity in early diagnosis.

The authors have declared no competing interest.

The author(s) received no specific funding for this work.

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