A patient’s capacity for tissue regeneration varies based on age, nutritional status, disease state, and lifestyle. Because regeneration rate cannot be predicted prior to biomaterial implantation, there is a need for responsive biomaterials with adaptive, personalized degradation rates to improve regenerative outcomes. Our research demonstrates an approach to use therapeutic ultrasound to alter the degradation profile of silk fibroin biomaterials noninvasively, post-implantation. By evaluating changes in weight, porosity, surface morphology, compressive modulus, and chemical structure, we conclude that therapeutic ultrasound can induce degradation of silk scaffolds. Furthermore, the scaffold’s mechanical properties and polymer structure were not altered during sonication. This method proved safe for human cells with no negative effects on cell viability or metabolism. Sonication through human skin also effectively triggered scaffold degradation, increasing the clinical relevance of these results. These findings suggest that silk is an ultrasound-responsive biomaterial, where degradation can be triggered noninvasively to improve regenerative outcomes.