The dynamic interplay between vascular smooth muscle cells (VSMCs) and the immune microenvironment governs vascular repair and disease progression. This review systematically elucidates this multidimensional regulatory network. We primarily dissect the molecular mechanisms driving pathological VSMC remodeling, encompassing inflammatory signaling, regulated cell death, senescence-associated DNA damage, and organelle dysfunction. Furthermore, we delineate the bidirectional crosstalk connecting VSMCs with the extracellular matrix (ECM) and tissue-infiltrating leukocytes, notably macrophages, T cells, and neutrophils. Subsequently, we evaluate how this network dictates disease-specific pathophysiology across various cardiovascular diseases. Specifically, we analyze metabolic reprogramming and epigenetic regulation in atherosclerosis (AS), mechanosensitive inflammation-contraction coupling in hypertension, and kinase-driven organelle stress in aortic aneurysms and dissection. Moreover, we examine the secretory profile of VSMCs in pulmonary arterial hypertension (PAH) and their contribution to microvascular dysfunction in arteritis and cardiomyopathy. Ultimately, we highlight emerging therapeutic strategies targeting VSMC-immune interactions and discuss future translational prospects.