Sericin has been exploited as a biomaterial due to its biocompatibility, biodegradability, and low-immunogenicity as an isolated polymer and support for cell adhesion. In the present study, human platelet-derived growth factor (PDGF-BB)-functionalized sericin hydrogels were generated using transgenic silkworms, where the as-spun silk incorporated engineered PDGF-BB (termed PDGFM) in the sericin layers of the cocoons. Sericin and PDGFM were simultaneously extracted from the silk fibroin cocoon fibers, and the soluble extract was then formed into a hydrogel via thermal exposure. The PDGFM sericin hydrogels exhibited increased β-sheet content and a compressive modulus of 74.91 ± 2.9 kPa comparable to chemically crosslinked sericin hydrogels (1.68-55.53 kPa) and a porous microstructure, which contributed to cell adhesion and growth. A 13.1% of total extracted PDGFM from the initial silk fibers was incorporated and immobilized in the sericin hydrogels during material processing, and 1.33% of PDGFM was released over 30 days from the hydrogels in vitro. The remaining PDGFM achieved long-term storage/stability in the sericin hydrogels for more than 42 days at 37 °C. In addition, the PDGFM sericin hydrogels were not immunogenic, were biocompatible and bioactive in promoting the support of cell proliferation. When combined with BMP-9, the PDGFM sericin hydrogels provided synergy to support the osteoblastic differentiation of mesenchymal stem cells (hMSCs) in vitro and in vivo. This study demonstrates that genetically functionalized PDGFM sericin hydrogels can provide useful biomaterials to support cell and tissue outcomes, here with a focus on osteogenesis.