The ABO blood group is closely related to clinical blood transfusion, transplantation, and neonatal hemolytic disease. It is also the most clinically significant blood group system in clinical blood transfusion. The purpose of this paper is to review and analyze the clinical application of the ABO blood group. The most common ABO blood group typing methods in clinical laboratories are hemagglutination test and microcolumn gel test, while genotype detection is mainly adopted in clinical identification of suspicious blood types. However, in some cases, the expression variation or absence of blood type antigens or antibodies, experimental techniques, physiology, disease, and other factors affect the accurate determination of blood types, which may lead to serious transfusion reactions. The mistakes could be reduced or even eliminated by strengthening training, selecting reasonable identification methods, and optimizing processes, thereby improving the overall identification level of the ABO blood group. ABO blood groups are also correlated with many diseases, such as COVID-19 and malignant tumors. Rh blood groups are determined by the RHD and RHCE homologous genes on chromosome 1 and are classified as Rh negative or positive according to the D antigen., the agglutination method is often used in clinical settings, while genetic and sequencing methods are often used in scientific research. Accurate ABO blood typing is a critical requirement for the safety and effectiveness of blood transfusion in clinical practice. Most studies were designed for investigating rare Rh blood group family, and there is a lack of research on the relationship between Rh blood groups and common diseases.