Triggering receptor expressed on myeloid cells 1 (TREM-1) is a critical amplifier of innate immune responses, orchestrating pathophysiology across diverse inflammatory conditions. In the oral cavity, TREM-1 activation promotes the development of periodontitis, peri-implantitis, and oral lichen planus by polarizing myeloid cells toward a pro-inflammatory state, enhancing pro-inflammatory cytokine release, and accelerating tissue degradation and bone resorption. Notably, this TREM-1-driven myeloid dysregulation also underpins severe systemic comorbidities, including atherosclerotic cardiovascular disease (ASCVD), diabetic kidney disease (DKD), and Alzheimer’s disease (AD). This review synthesizes current knowledge to delineate the TREM-1 axis as a pathogenic hub in oral-systemic crosstalk, specifying three dissemination routes: systemic leakage of local mediators after barrier disruption, peripheral migration of epigenetically primed TREM-1⁺ cells, and synergy with metabolic risks. We further highlight soluble TREM-1 (sTREM-1) as a promising biomarker reflecting cumulative inflammatory burden. Ultimately, combining established oral therapies with emerging TREM-1-targeted strategies offers a mechanistically grounded framework to disrupt the oral-systemic disease continuum, providing novel therapeutic avenues for inflammatory comorbidities.