Skin defects are an important and pressing clinical problem. The use of hydrogels as a regenerative scaffold presents a promising approach to cure skin defects by inducing dermal reconstruction. Although synthetic material hydrogels display good mechanical properties, their poor biocompatibility restricts their application. To develop a good dermal substitute, we have successfully prepared hydrogels that mimic the extracellular matrix of the human body and can be used for tissue engineering skin scaffolds. The hydrogels were synthesized by adding hyaluronic acid (HA) and carboxylated chitosan (CCS) to human-like collagen (HLC) that can be used to tissue engineering skin scaffolds and using transglutaminase as a crosslinking agent. The mechanical characteristics of the hydrogels were explored by cyclic compressive mechanical tests and a uniaxial tension protocol. The compressive stress of HLC/HA/CCS (GEL4) hydrogel reached 0.2136 +/- 0.034 MPa when the compressive strain reached 60%. The tensile strain of GEL4 was 126.99 +/- 2.38%. The hydrogels significantly promoted adhesion, proliferation and migration of L929 cells, demonstrating the good biocompatibility of the hydrogels. For in vivo analysis, we constructed a full-thickness skin defect model and demonstrated that the hydrogels could effectively prevent invasion of the wound by outside bacteria and certificate that they are beneficial in promoting wound healing over pathologic healing. Subcutaneous implantation experiments revealed that the degradation period of the hydrogels with HA and CCS is suitable for the healing cycle of skin tissue, and the inflammatory reaction could be reduced to a very short time, indicating the good histocompatibility of the hydrogels. Therefore, the hydrogels are favourable, soft and porous materials that demonstrate good potential for skin repair, drug delivery, cartilage treatment and other tissue engineering applications.