There is a compelling need to find new materials that meet stringent performance requirements for application in food, water, and agriculture industries while addressing biodegradability, circular life cycle, and sustainable sourcing at scale. Regenerated silk fibroin (SF) is a structural biopolymer with applications in biomedicine, optoelectronics, food, water, and agriculture. Extracted from largely available Bombyx mori cocoons through a water-based process, SF is fabricated into advanced materials that have competitive performance and merits of natural origin and nontoxicity. As a protein, SF is considered slowly degradable in the human body, but as a material, it is known to be environmentally stable, and its biodegradation is mostly unknown. In this study, the degradation of SF in different soil and water environments is investigated. The effects of SF polymorphism, ionic strength, and the presence of microorganisms on proteinaceous material degradation are investigated. Modulation of beta-sheet content allowed us to control the degradation rate of SF films in soil of increasing NaCl concentration. Microbial activity was a key driver for silk degradation under different environmental conditions. Bacterial colonization accelerated silk film degradation, a process that was further enhanced by encapsulation of bacteria in SF materials at the point of material assembly. Together, these data show that SF biodegradation can be controlled by material design and by regulating the interaction with microorganisms present in the environment.