Plants require a fine balance of zinc (Zn) for proper growth and development. This fine-tuning of Zn metabolism is tightly regulated and often challenging task for plants. Hyperaccumulating ecotype of Sedum alfredii Hance, a Zn hyperaccumulator form the Crassulaceae family, offers a unique model to study Zn homeostasis. To date, their complex molecular mechanisms underlying Zn regulation remain largely unknown. Here, we present a large-scale comparative investigation of Zn homeostasis networks in Zn hyperaccumulating and non-hyperaccumulating ecotypes of S. alfredii. By integrating transcriptomics, proteomics, metabolomics, and ionomics, we uncovered that transcriptional and translational changes play critical roles in maintaining Zn homeostasis. These adaptations include enhanced photosynthetic efficiency, improved Zn ion binding in shoots, and increased antioxidative capacities. Additionally, carbon and sulfur metabolic pathways were found to respond significantly to Zn treatment. Key components of the tricarboxylic acid (TCA) cycle, along with stress-related amino acids, fatty acids, sugars, antioxidants, and Zn-binding phenolics, were coordinately modulated under Zn exposure. This multi-omics integration provides novel insights into the functional genomics and metabolic adaptations of the Zn hyperaccumulator S. alfredii and will facilitate biotechnological applications of Zn hyperaccumulation traits for biofortification, phytoremediation and food crop safety.