In this study, we fabricated multifunctionalized hydrogel scaffolds based on hyaluronic acid (HA)-tyrosine and human-like collagen (HLC) by crosslinking with 1, 4-butanedioldiglycidyl ether (BDDE) for soft tissue fillers. The physicochemical of HA-tyrosine/BDDE (HTB) and various proportions of HA-tyrosine/BDDE/HLC (HTBH) hydrogels were characterized by swelling ratio, mechanical strength, morphology and thermal stability. The results demonstrated various HTBH hydrogels had superior performance in mechanical properties than HTB hydrogels. The biodegradation in vitro results demonstrated the degradation of HTBH hydrogels were slower than HTB hydrogels, and residual masses of HTBH hydrogels varied with different proportions of HA-tyrosine and HLC in the presence of the combination of HAse/collagenase I. The cell counting kit-8 (CCK-8), Hoechst/PI staining and cell adhesion of various HTBH hydrogels showed less cytotoxic and superior fibroblast attachment than those of HTB hydrogels. Moreover, subcutaneous injections of HTBH hydrogels containing high proportions of HLC in mice and rabbits all exhibit better biocompatibility and anti-biodegradation compared to HTB hydrogels after 1, 4, 8, 12 and 16 weeks. Hematoxylin-eosin staining (H&E), immunohistochemical and transmission electron microscope (TEM) analysis results indicated HTBH hydrogels had less intense inflammatory responses with increase proportion of HLC. Taken together, HTBH hydrogels had great potential application as ideal soft tissue fillers with excellent mechanical properties, biological stability and biocompatibility.