Blend drug-loading method in electrospun scaffolds has gained much attention as a cost-effective and simple delivery system in regenerative medicine. However, it has some drawbacks, such as the burst release of encapsulated drugs and denaturing active agents in harsh organic solvents. In this study, a new silk fibroin-gelatin (SF-G) fibrous sheet has been introduced as an engineered scaffold and a straightforward drug delivery system for skin tissue engineering applications. The hybrid sheets have been prepared via co-electrospinning and in-situ crosslinking methods without corrosive solvents and toxic crosslinking agents. To evaluate the proposed scaffold as a controlled release system, the simvastatin (SIM), a poorly water-soluble drug, and bovine serum albumin (BSA), a hydrophilic protein, have been selected as two model pharmaceutical ingredients. The physicochemical and mechanical properties, as well as the degradation profile of the hybrid sheets, indicate that the fabrication method, SF: G fibers volume ratio and degree of crosslinking are vital in controlling the different features of the prepared scaffolds. The obtained results demonstrate that the hybrid structure, type of fiber, and in-situ crosslinking method provide an opportunity to adjust the release kinetics of encapsulated drug/protein within the fiber matrix. The in-vitro analysis also demonstrates suitable bioactivity of the drug/protein-loaded scaffolds. Therefore, this hybrid nanofibrous sheet may be considered a new candidate for biomedical applications and pharmaceutical science.