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Regeneration of large bone defects is challenging in the next few years because the age of the population is growing. Bone grafting as a gold standard of bone repairing is limited as a result of many disadvantages. In recent years, many novel materials and processing methods have been introduced to construct the native bone extracellular matrix (ECM) and restore the functions of degenerated bone. Silk fibroin (SF) as a natural polymer, has established a good reputation for bone tissue engineering applications due to its many unique properties, including exceptional biocompatibility, biodegradability, mechanical behavior, and ease of processability. In this review, recent advances in the design and application of SF-based scaffolds for bone regeneration are discussed.