Natural polymers have been used in the biomedical fields for decades, mainly derived from animals and plants with high similarities with biomacromolecules in the human body. As an alkaline polysaccharide, chitosan (CS) attracts much attention in tissue regeneration and drug delivery with favorable biocompatibility, biodegradation, and antibacterial activity. However, to overcome its mechanical properties and degradation behavior drawbacks, a robust fibrous protein-silk fibroin (SF) was introduced to prepare the CS/SF composites. Not only can CS be combined with SF via the amide and hydrogen bond formation, but also their functions are complementary and tunable with the blending ratio. To further improve the performances of CS/SF composites, natural (e.g., hyaluronic acid and collagen) and synthetic biopolymers (e.g., polyvinyl alcohol and hexanone) were incorporated. Also, the CS/SF composites acted as slow-release carriers for inorganic non-metals (e.g., hydroxyapatite and graphene) and metal particles (e.g., silver and magnesium), which could enhance cell functions, facilitate tissue healing, and inhibit bacterial growth. This review presents the state-of-the-art and future perspectives of different biomaterials combined with CS/SF composites as sponges, hydrogels, membranes, particles, and coatings. Emphasis is devoted to the biological potentialities of these hybrid systems, which look rather promising toward a multitude of applications.