Establishing an appropriate degradation rate is critical for tissue engineering scaffolds. In this study, the degradation rate of silk fibroin three-dimensional scaffolds was regulated by changing the molecular weight (MW) of the silk fibroin. The solubility of silk fibroin depends primarily on the ionic ability of the slovent to dissolve silk fibroin, therefore, we regulated the MW of the silk fibroin using LiBr, Ca(NO₃)₂ and CaCl₂ to dissolve the silk fibers. SDS-PAGE analysis showed that the MW of the CaCl2-derived silk fibroin was lower than the MW produced using LiBr and Ca(NO₃)₂. In vitro and in vivo degradation results showed that the scaffolds prepared by low-MW silk fibroin were more rapidly degraded. Furthermore, FTIR and amino acid analysis suggested that the amorphous regions were preferentially degraded by Collagenase IA, while the SDS-PAGE and amino acid analysis indicated that the scaffolds were degraded into polypeptides (mainly at 10-30 kDa) and amino acids. Because the CaCl₂-derived scaffolds contained abundant low MW polypeptides, inter-intramolecular entanglement and traversing of molecular chains in the crystallites reduced, which resulted in rapid degradation. The in vivo degradation results suggested that the degradation rate of the CaCl₂-derived scaffolds was better matched to dermis regeneration, indicating that the degradation rate of silk fibroin can be effectively regulated by changing the MW to achieve a suitable dermal tissue regeneration rate.