The inherited genetic disorder β-thalassemia affects the hematopoietic system and is caused by low production or absence of adult hemoglobin (HbA). Ineffective erythropoiesis is the hallmark of β-thalassemia pathophysiology and is characterized by an erythropoietin-driven substantial increase in erythroblast proliferation, coupled with an increase in late-stage precursor apoptosis, which results in low levels of circulating mature red blood cells (RBCs) and chronic anemia. Mitochondrial dysfunction commonly occurs in these cells because of the increased demand for energy production and the need to manage abnormal hemoglobin chain synthesis. Moreover, several studies have highlighted the importance of gradual mitochondrial clearance for mature erythroid cell production. In this review, we presented the available information on the role of mitochondria in vital cellular processes, which makes them promising pharmacological targets for maintaining the health and function of RBCs.