Intimal hyperplasia, a pathological form of vascular remodeling, is a hallmark of several cardiovascular diseases, including restenosis following angioplasty. Vascular smooth muscle cell (VSMC) phenotypic transition plays a critical role in the development of vascular intimal hyperplasia. This study investigates the role of the NOD-like receptor pyrin domain 3 (NLRP3) inflammasome and its downstream effector, gasdermin D (GSDMD), in regulating VSMC phenotypic transition and their implications in the development of intimal hyperplasia. In primary cultured VSMCs, platelet-derived growth factor BB (PDGF-BB) stimulated activation of the NLRP3-GSDMD axis, promoting inflammation, proliferation, and migration. Pharmacological inhibition of the inflammasome with the caspase-1 inhibitor YVAD significantly attenuated PDGF-BB-induced GSDMD activation and lactate dehydrogenase release. Furthermore, silencing the Gsdmd gene effectively blocked PDGF-BB-induced VSMC proliferation, migration, and inflammatory responses. In vivo, intimal hyperplasia was modeled by performing carotid artery ligation in hypercholesterolemic mice. In Nlrp3(+/+) mice, vascular injury led to increased inflammasome and GSDMD activation, enhanced pyroptosis, elevated vascular inflammation, macrophage infiltration, and a shift to a synthetic VSMC phenotype, primarily within the VSMC-rich intimal region. In contrast, these pathological changes were significantly attenuated in Nlrp3(-/-) mice. These findings provide novel insights into the critical role of the NLRP3-GSDMD axis in VSMC phenotypic transition and vascular injury-induced intimal hyperplasia, suggesting that targeting this pathway may offer a promising therapeutic strategy for cardiovascular diseases characterized by intimal hyperplasia.NEW & NOTEWORTHY This study reveals that the NLRP3-GSDMD axis drives PDGF-BB-induced dedifferentiation transition and inflammation of vascular smooth muscle cells (VSMCs), contributing to intimal hyperplasia. These findings identify NLRP3-GSDMD signaling as a novel driver of pathological vascular remodeling and a potential therapeutic target for intimal hyperplasia-associated cardiovascular diseases.