As central mediators bridging innate and adaptive immunity, macrophages exhibit functional plasticity that is precisely governed by dynamic epigenetic networks, The histone H3K27 demethylase KDM6B acts as a key epigenetic hub that mediates the epigenetic remodeling of macrophages in response to environmental signals and exerts pleiotropic regulatory roles across diverse pathophysiological contexts. In the tumor microenvironment, KDM6B drives the polarization of tumor-associated macrophages toward an M2-like immunosuppressive phenotype, reshapes cellular metabolism, and consequently promotes tumor immune escape and progression. Similarly, in inflammatory and autoimmune diseases, KDM6B acts as a core epigenetic regulator of the NF-κB pathway, initiating and sustaining chronic inflammation by modulating inflammasome activity and accelerating cytokine release. In fibrotic diseases, KDM6B facilitates macrophage M2 polarization and their transdifferentiation into myofibroblasts, positioning itself as a central driver of organ fibrosis initiation and progression. In infectious diseases, KDM6B plays a dual role: it enhances antiviral immune responses to strengthen host defense, yet can also be hijacked by pathogens such as Leishmania donovani and mycobacteria, which induce an immunosuppressive phenotype in macrophages that facilitates pathogen survival. Beyond these contexts, KDM6B also regulates the function of tissue-resident macrophage subsets including microglia, thereby participating in pathophysiological processes such as neuroinflammation and maternal-fetal tolerance. Collectively, KDM6B-mediated regulation of macrophages is highly dependent on the microenvironment, conferring both promising therapeutic potential and practical challenges. Further elucidation of its precise regulatory circuits in distinct pathological microenvironments will be essential for the development of targeted therapeutic strategies.