Sickle cell disease (SCD) is a recessively inherited blood disease. Although being monogenic, the phenotypes are markedly diverse. Different studies have confirmed that the deregulation of microRNAs (miRNAs) boosts the clinical severity or has a modulatory effect in SCD. MiR-144 has been claimed to be a contributing factor for the impaired oxidative stress tolerance and aggravated anemia in SCD. Thus, the present investigation intends to assess the relative expression of miR-144 in 40 SCD patients to validate its role in relation to clinical phenotype and HbF production. Forty SCD cases and 40 healthy individuals were studied in the current research. Patients were genotyped by direct sequencing of the HBB gene. The expression of miR-144 was assessed by real-time PCR (qRT-PCR). Thirty cases (75%) were SS and 10 cases (25%) were S/β. MiR-144 was upregulated in SCD cases in relation to controls (P = 0.015). MiR-144 was positively correlated to the frequency of painful episodes (p = 0.0001). It was also associated with vertigo in the examined cases. Concerning HbF, an inverse correlation was observed in regards to the miR-144 expression without achieving the significance level. In conclusion, miR-144 could be a prospective genetic marker of disease outcome and targeted therapy in sickle cell disease. MiRNA mimics and antagomirs may be future therapeutic agents stimulating HbF production and thus potentially alleviating the clinical sequalae of SCD.