Hypoxia is a characteristic feature of the atherosclerotic plaque microenvironment and a critical driver of vascular remodeling. However, the dynamic transition of metabolic networks in vascular smooth muscle cells (VSMCs) remains incompletely understood. In this study, we performed a time-resolved analysis (0, 12, 24, and 48 h) of hypoxic VSMCs, utilizing integrated proteomics and metabolomics to map their temporal molecular landscape. Our data revealed a progressive impairment of mitochondrial oxidative phosphorylation, supported by a broad downregulation of oxidative pathway components and the validated suppression of key Complex I subunits. Conversely, central carbon metabolism underwent rapid and sustained upregulation at the protein level, marked by the induction of glucose transporter GLUT1 and key glycolytic enzymes including HK1/2, PFKFB3, GAPDH, ENO1, and PKM. Notably, while glycolytic enzyme levels increased consistently, their corresponding metabolic intermediates exhibited heterogeneous temporal fluctuations rather than simple accumulation. Furthermore, we identified a time-dependent shift in nitrogen and redox homeostasis, specifically the diversion of arginine metabolism toward the ornithine–polyamine pathway, alongside a gradual depletion of the reduced glutathione pool. Collectively, these findings demonstrate that hypoxia drives a highly coordinated and stage-specific metabolic adaptation in VSMCs, providing a systematic map of the metabolic reprogramming underlying vascular cell function in the hypoxic plaque microenvironment.