Thalassemia is a hematological disorder caused by a gene mutation that leads to defective synthesis of hemoglobin complex. One of the complications of thalassemia is hypocalcemia which is presented with paresthesia, muscle spasm, low-serum calcium, and intracranial calcification. Hypocalcemia can affect thalassemic patients via various mechanisms. Blood transfusion-related and transfusion-independent iron overload, drug side effects, vitamin D3 deficiency, and genetic disorders and polymorphisms are among the etiologies of hypocalcemia in major thalassemia. A careful approach to the differential etiology of this phenomenon is crucial for a resultful treatment.