The discovery of hemoglobin variants with low oxygen affinity, diagnostic methods, prognosis of carriers, and developments in analyzing hemoglobin oxygen-carrying and -releasing abilities are reviewed in this article in order to draw the attention of related clinical departments and to provide references for optimizing the process of diagnosis and treatment. Hemoglobin variants with low oxygen affinity originate from gene mutations encoding hemoglobin and autosomal dominant inheritance. The diagnosis should be combined with clinical manifestations and family history and differentiated from methemoglobinemia. A decrease in pulse oxygen saturation (SpO₂) is often the first abnormality observed in asymptomatic carriers of hemoglobin variants with low oxygen affinity. Laboratory examinations include arterial blood gas analysis, hemoglobin oxygen affinity testing, protein analysis and gene sequencing. Most carriers do not require specific treatment and have a good prognosis, who should avoid acute hypoxic injuries induced by strenuous exercise, emotional stress, or high temperature. Moreover, health practitioners should pay attention to their responses to anesthetics, agents that induce oxidative stress, drugs that increase hemoglobin oxygen affinity, and prostacyclins. Hemoglobin oxygen-carrying and-releasing analysis is a promising tool to identify carriers of hemoglobin variants with low oxygen affinity because it does not involve unnecessary or invasive examinations and is of significant values for clinical diagnosis and treatment.