Macrophages are pivotal regulators of immunity, playing dual roles in both propagating and resolving inflammation through their remarkable plasticity. Their ability to polarize into pro-inflammatory (M1) or anti-inflammatory (M2) phenotypes makes them attractive targets for treating diseases ranging from cancer to chronic inflammatory disorders. However, precise control over macrophage polarization remains a therapeutic challenge. Recent advances in nanomaterial engineering have unlocked unprecedented opportunities to direct macrophage polarization with high specificity, offering novel strategies for immunomodulation and tissue repair. This review systematically examines the latest breakthroughs in nanomaterial-driven macrophage reprogramming, focusing on how tailored physicochemical properties (e.g., size, surface charge, and composition) of organic, inorganic, and hybrid nanoparticles influence phenotypic outcomes. We highlight key signaling pathways (e.g., NF-κB, STAT, TLR) and biomarkers (e.g., cytokines, metabolic shifts) modulated by nanomaterials, linking these mechanisms to therapeutic applications in cancer immunotherapy, infectious diseases, and regenerative medicine. Furthermore, we discuss emerging trends such as stimuli-responsive nanomaterials and combination therapies that enhance spatiotemporal control over polarization. By bridging gaps between nanotechnology and immunology, this work not only catalogs current achievements but also outlines future directions for precision nanomedicine, advocating for clinically translatable solutions to harness macrophage plasticity for disease therapy.