Phosphofructokinase, muscle type (PFKM), is a key rate-limiting enzyme in the glycolytic pathway, and its expression and activity are regulated by multiple signaling pathways, including HIF-1α, Myc, PI3K/AKT, and AMPK. Recent studies have demonstrated that PFKM can reprogram macrophage function by modulating glycolytic processes. On one hand, PFKM drives classical macrophage activation through the canonical glycolytic pathway, thereby promoting bactericidal and antitumor activities. On the other hand, emerging evidence indicates that PFKM also exerts “non-canonical” functions independent of its enzymatic activity, inhibiting macrophage phagocytosis and contributing to the formation of an immunosuppressive microenvironment. Importantly, physicochemical factors in the microenvironment, including mechanical forces, glucose, and citrate, can shift the equilibrium between the tetrameric and dimeric conformations of PFKM, thereby facilitating the switch between its classical and non?classical functions. While current research has largely focused on the classical glycolytic role of PFKM, its non?canonical functions and the underlying molecular mechanisms remain to be fully elucidated. This review summarizes the classical and non?canonical roles of PFKM in macrophages, its upstream regulatory signals, and its implications in infectious diseases and cancer, aiming to provide a theoretical foundation and insights for PFKM?targeted immunometabolic therapeutic strategies.