Chronic blood transfusion remains the most feasible therapeutic option for the majority of patients with severe β-thalassemia. However, it is associated with serious risks and complications. An alternative option is desirable and may prevent some of the problems associated with current therapy. Hydroxyurea (HU), an oral chemotherapeutic drug, is expected to increase hemoglobin, thereby minimizing the burden of blood transfusion and its complications. The objective of this study was to conduct a systematic review and meta-analysis to evaluate the clinical efficacy and safety of HU in patients with severe β-thalassemia. HU appears to be effective, well tolerated and associated with mild and transient adverse events; however, large randomized clinical trials (RCTs) should be done to confirm such findings. Nonetheless, based on the results of the present meta-analysis, it is recommended that current practice guidelines for severe β-thalassemia be appended to include a trial of HU.