Hyaluronic acid is a naturally derived glycosaminoglycan (GAG) involved in biological processes. A low molecular weight hyaluronic acid (50 kDa)-based hydrogel was synthesized using acrylated hyaluronic acid. Matrix metalloproteinase (MMP) sensitive hyaluronic acid-based hydrogels were prepared by conjugation with two different peptides: cell adhesion peptides containing integrin binding domains (Arg-Gly-Asp: RGD) and a cross-linker with MMP degradable peptides to mimic the remodeling characteristics of natural extracellular matrices (ECMs) by cell-derived MMPs. Mechanical properties of these hydrogels were evaluated with different molecular weights of acrylated hyaluronic acid (10 kDa and 50 kDa) cross-linked by MMP sensitive peptides by measuring elastic modulus, viscous modulus, swelling ratio and degradation rate. The MMP sensitive hydrogel based on the 50 kDa hyaluronic acid showed a 31.5-fold shorter gelation time, 4.7-fold higher storage modulus and 0.51-fold smaller swelling ratio than those of the hydrogel based on the 10 kDa. Degradation rate was dependent on MMP sensitivity of the peptide cross-linker. MMP sensitive hyaluronic acid based hydrogels were degraded faster than MMP insensitive-hyaluronic acid-based hydrogels. Human mesenchymal stem cells (MSCs) were cultured in MMP-sensitive or insensitive hyaluronic acid-based hydrogels (50 kDa hyaluronic acid) and/or immobilized cell adhesive RGD peptides. Cells cultured in the MMP-sensitive hydrogel with RGD peptides showed dramatic cell spreading compared with that of the control, which remained round. This MMP-sensitive low molecular weight hyaluronic acid-based hydrogel could be useful in tissue engineering by improving tissue defect regeneration and tissue remodeling.