Cellular energetics plays an important role in tissue regeneration, and the enhanced metabolic activity of delivered stem cells can accelerate tissue repair and regeneration. However, conventional hydrogels with limited network cell adaptability restrict cell-cell interactions and cell metabolic activities. In this work, it is shown that a cell-adaptable hydrogel with high network dynamics enhances the glucose uptake and fatty acid β-oxidation of encapsulated human mesenchymal stem cells (hMSCs) compared with a hydrogel with low network dynamics. It is further shown that the hMSCs encapsulated in the high dynamic hydrogels exhibit increased tricarboxylic acid (TCA) cycle activity, oxidative phosphorylation (OXPHOS), and adenosine triphosphate (ATP) biosynthesis via an E-cadherin- and AMP-activated protein kinase (AMPK)-dependent mechanism. The in vivo evaluation further showed that the delivery of MSCs by the dynamic hydrogel enhanced in situ bone regeneration in an animal model. It is believed that the findings provide critical insights into the impact of stem cell-biomaterial interactions on cellular metabolic energetics and the underlying mechanisms.