Understanding the biophysical relationships between stem cells and applied biomaterials can facilitate the ability to control the functions and behaviors of stem cells. However, the role of 3D microenvironment in stem cell biology remains largely unexplored, compared with that of 2D cell‐culture environment. Here, a new strategy that improves the efficacy of Yamanaka's four‐factor‐induced cellular reprogramming into induced pluripotent stem cells (iPSCs) by incorporating cues derived from the 3D microenvironment and biophysical ligands is reported. Among the various 3D hydrogel systems tested, methacrylated hyaluronic acid (HA) hydrogel significantly improves cellular reprogramming into iPSCs. Additionally, the initial upregulation of CD44 in encapsulated cells in low‐level methacrylated soft HA hydrogel accelerates the reprogramming. In conclusion, the reported HA hydrogel with low modulus accelerates reprogramming into iPSCs and thus offers potential advantages for translational applications.