MicroRNAs (miRNAs) involving miR-145-5p and miR-133a-3p are increasingly recognized for their roles in modulating inflammation, oxidative stress, and vascular integrity, key processes implicated in sickle cell disease (SCD) pathophysiol ogy. To investigate the expression levels of miR-145-5p and miR-133a-3p in pediatric SCD patients during vaso-occlusive crisis (VOC) as well as steady-state conditions, and to evaluate their potential as clinical biomarkers. A case-control study was conducted including 45 pediatric SCD patients (24 during VOC and 21 in steady-state) and 45 age- and sex matched healthy controls. Plasma miR-145-5p and miR-133a-3p levels were quantified using real-time quantitative PCR and correlated with clinical characteristics, laboratory parameters, genotype, and hydroxyurea (HU) therapy. Circulat ing miR-133a-3p and miR-145-5p were significantly higher in SCD patients than in controls (p < 0.001), with a further elevation during VOC compared to steady-state (p < 0.050). While no significant association was found with genotype or HU therapy (p > 0.05), miR-133a-3p levels correlated significantly with fetal hemoglobin (HbF) (p = 0.006), reticulo cyte count (p = 0.049), and urine albumin/creatinine ratio (p = 0.043). A strong positive correlation was observed between both miRNAs (r = 0.683, p < 0.001). Receiver Operating Characteristic (ROC) analysis demonstrated reasonable diagnostic accuracy of both miRNAs in distinguishing VOC from steady-state (AUC = 0.69). This study highlights the potential of miR-133a-3p and miR-145-5p as biomarkers for SCD activity. The association of miR-133a-3p with HbF and urine A/C ratio further suggests clinical relevance in vaso-occlusive complications. Larger longitudinal and functional studies are needed to validate these findings.