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Type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD) are closely linked cardiometabolic disorders that share common inflammatory, metabolic, and vascular mechanisms. However, the molecular mediators underlying their interconnected pathophysiology remain incompletely understood. Orosomucoid 2 (ORM2), a hepatocyte-derived acute-phase glycoprotein, has emerged as a potential mediator at the interface of metabolic and vascular dysfunction. Experimental and clinical evidence suggests that ORM2 plays important roles in hepatic lipid metabolism, insulin sensitivity, and immune regulation. Reduced ORM2 expression has been reported in obesity and insulin-resistant states, while circulating orosomucoid levels have been associated with diabetic nephropathy, microalbuminuria, and long-term risk of myocardial infarction. Mechanistically, ORM2 suppresses hepatic de novo lipogenesis through AMP-activated protein kinase signaling, improves glucose homeostasis by modulating interferon-γ/STAT1 signaling in adipose tissue, and regulates liver macrophage polarization via an inositol 1,4,5-trisphosphate receptor type 2-dependent calcium pathway. Preclinical studies further demonstrate that recombinant ORM2 attenuates atherosclerosis, hepatic steatosis, and steatohepatitis without detrimental metabolic effects, supporting its potential therapeutic relevance. Notably, ORM2 is regulated by pro-inflammatory cytokines, including interleukin-1β, interleukin-6, and tumor necrosis factor-α, which are central to the pathogenesis of both T2DM and CAD. Collectively, these findings position ORM2 as a promising integrative biomarker and therapeutic target within the adipose-liver-vascular axis. Further prospective clinical studies, Mendelian randomization analyses, and tissue-specific experimental models are needed to clarify its causal role in the shared pathophysiology of T2DM and CAD.