Sickle cell disease (SCD) and thalassemia are common inherited blood disorders in Saudi Arabia, especially in Jazan Province. Patients with these disorders require multiple blood transfusions, which may lead to alloimmunization because of mismatched blood group antigens. In this study, we examined the alloimmunization and autoimmunization rates in patients with SCD and thalassemia together with the involved antibodies. A cross-sectional study was conducted to review the transfusion history records of patients with SCD and thalassemia at Prince Mohammed bin Nasser Hospital, Jazan Province, Saudi Arabia. Four-hundred thirty-eight patients (385 with SCD, 52 with β-thalassemia, and 1 with α-thalassemia) were received leukoreduced red cell transfusions. The alloimmunization and autoimmunization rates in patients with SCD were 12.98% and 0.52%, respectively. In patients with thalassemia, the alloimmunization and autoimmunization rates were 13.21% and 3.77%, respectively. The most prevalent antibodies in the study population were anti-E (17.19%) and anti-K (14.06%). The alloimmunization and autoimmunization rates were determined in patients with SCD and thalassemia in Jazan Province, Saudi Arabia. The results highlight the need for extended phenotyping to include ABO, RH (D, C, c, E, e), K, Fya, Fyb, Jka and Jkb antigens in the screening panel. This will benefit patients to ensure better transfusion practices.