Vascular smooth muscle cell (vSMC) phenotypic modulation is a dynamic pathogenesis process implicated in neointimal formation and transplant arteriosclerosis (TA). Transcription factor Sox9 functions to establish cell type and wound healing, but little is known about its transcriptional regulation in vSMCs and its roles in the development of TA. Here, we found an increased Sox9 expression in aortic allografts and in HMGB1-treated vSMCs in vitro, accompanied by the downregulation of vSMC markers. Notably, vSMC-specific Sox9 knockdown in aortic allografts attenuated neointimal formation through preventing vSMC phenotypic modulation following transplantation. We further indicated that HMGB1 induced Sox9 expression and vSMC phenotypic modulation through activating autophagy to degrade p27(Kip1). Mechanistically, p27(Kip1) bound to the Sox9 promoter in vSMCs together with p130/E2F4 complex, by which it restrained Sox9 transcriptional expression. These findings uncover a fundamental role of Sox9 in mediating autophagy-dependent vSMC phenotypic modulation and TA, offering a therapeutic approach for vascular pathologies.