<p>Triggering receptor expressed on myeloid cells 2 (TREM2), a crucial immunomodulatory receptor expressed on myeloid cells, is pivotal in regulating immune responses and maintaining tissue homeostasis. TREM2 has gained prominence as a key factor in deciphering the pathological mechanisms of diverse diseases, particularly due to its significant influence on macrophage function in disease progression. The TREM2 signaling pathway governs macrophage activation, polarization, phagocytosis, and cytokine secretion, thereby impacting immune regulation and the progression of inflammation. Dysregulation of TREM2-mediated macrophage function is closely linked to the pathogenesis of multiple systemic diseases. Specifically, in the central nervous system, extensive research has focused on TREM2’s regulatory influence on microglial function. Concurrently, its pathogenic roles in disorders beyond the neurological spectrum have increasingly garnered investigative attention. This review offers a structured overview of recent advances in understanding the mechanisms through which TREM2 regulates macrophage function and its implications in non-neurological diseases. Particular emphasis is placed on the potential of TREM2 as a therapeutic target for modulating macrophage-mediated pathological processes.</p>