With the efficient cross-linking abilities and the flexible regulation abilities to the performances of cross-linked products, the multi-functional aliphatic epoxides were once widely used to cross-link the collagen-based materials in the last century. In present work, the multi-functional epoxides were used to construct and cross-link collagen sponges for tissue engineering scaffolds, which was hoped to board the theoretical system of epoxides and explore their potentials for modern applications. The bi- to tetra-functional epoxides were used to cross-link collagen solutions and establish the gel-like precursors, then using freeze-drying to form the final sponges. The SEM observed that the sponges had shown regular porous structures with a wide range of pore sizes from 160 to 440 μm. The sponges had presented the resistance to enzymatic degradation, shape-remaining ability, and reversible compressibility in aqueous environments, which all could be regulated through the functionalities of epoxides. The regulation abilities of multi-functional epoxides on the performances of sponges had been mainly achieved through the cross-linking degrees that the higher functionality of epoxides would bring higher cross-linking degree. Such higher cross-linking degrees could enhance the elastic behaviors of gel-like precursors, and improve the compressive strengths and thermal stabilities of sponges. Nevertheless, the multi-functional epoxides had barely affected the safety of collagen sponges at the cellular level according to the results of CCK8 assay and the SEM and CLSM images of L929 fibroblasts cultured on the cross-sections of sponges.