To fabricate environmentally sensitive hydrogels with better biocompatibility, natural materials such as protein and polysaccharide have been widely used. Environmentally sensitive hydrogels can be used as a drug carrier for sustained drug release due to its stimulus responsive performance. The relationship between the internal structure of hydrogels and their drug delivery behaviors remains indeterminate. In this study, environmentally sensitive hydrogels fabricated by blending silk fibroin/chitosan with different mass ratios were successfully prepared using 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (EDC)/N-Hydroxysuccinimide (NHS) cross-linking agent. Scanning-electron microscopy (SEM) images showed the microcosmic surface of the gel had a 3-D network-like and interconnected pore structure. The N 2 adsorption-desorption method disclosed the existence of macroporous and mesoporous structures in the internal structure of hydrogels. Data of compression tests showed its good mechanical performance. The swelling performance of hydrogels exhibited stimuli responsiveness at different pH and ion concentration. With the increase of pH and ion concentration, the swelling ratios of hydrogels (silk fibroin (SF)/ chitosan (CS) = 8/2 and 7/3) decreased. Methylene blue (MB) was loaded into the hydrogels to confirm the potential of sustained drug release and pH-responsive behavior. Therefore, due to the porous structure, stable mechanical strength, stimuli responsive swelling performance, and drug release behaviors, the SF/CS composite hydrogels have potential applications in controlled drug release. of hydrogels prepared by chemical cross-linking is relatively stable. The physical properties of hydrogel are similar to the properties of living tissues, such as high water content, rubbery texture, and low interfacial tension, which contribute to its outstanding biocompatibility with the surrounding tissues [6]. The mechanical property, shape, and swelling performance of some hydrogels tend to change with the external conditions, such as temperature, pH value, and ion concentration [7][8][9]. Drugs can be delivered through hydrogels with stimuli responsiveness to pH, magnetism, ultrasound, temperature changes, and electrical effects [8]. The stimuli responsiveness of hydrogel makes it potential material for drug release, which has been proved in previous studies [10][11][12]. Cross-linking mechanism or pore structure of hydrogels may be the cause of stimuli responsiveness, which has not been revealed. In this study, a pH-and ion intensity stimuli-responsive silk fibroin/chitosan hydrogel was prepared by chemical cross-linking. The mechanism of stimulus responsiveness of the hydrogel was also indicated.Silk fibroin (SF) is a kind of natural material with high molecular weight, good biocompatibility, and mechanical strength [13]. Hydrogel made of silk fibroin has broad application prospects in artificial skin, wound dressing, sustained drug release, tissue engineering scaffolds, and so on [14-17]. Chitosan (CS) is a natural ba...