Glycolysis is an important step in respiration and provides energy for cellular processes. Pyruvate kinase M2 (PKM2), a key rate-limiting enzyme of glycolysis, plays an important role in tumor cell metabolism and proliferation. It is also specifically overexpressed in leukemia cells and contributes to leukemic proliferation, differentiation, and drug resistance through both aerobic glycolysis and non-metabolic pathways. In this review, the functions and regulatory roles of PKM2 are firstly introduced. Then, the molecular mechanisms of PKM2 in leukemogenesis are summarized. Next, reported PKM2 modulators and their anti-leukemia mechanisms are described. Finally, the current challenges and the potential opportunities of PKM2 inhibitors or agonists in leukemia therapy are discussed.