3D scaffolds based on embedding drug loaded calcium alginate beads within silk fibroin protein were fabricated for investigating controlled dual drug release. The 3D matrices were evaluated for in vitro release using two different molecular weight model compounds, bovine serum albumin (66 kDa) and FITC-Inulin (3.9 kDa). The model compound release profiles revealed dependence on molecular weight of encapsulated model drugs for sustained release. Further, silk fibroin protein blended calcium alginate beads resulted in prolonged drug release without initial bursts for 35 days as compared to calcium alginate beads without silk fibroin as control. The release kinetics were further tested as a function of wt% silk content for scaffold fabrication suggesting their possible role in restricting initial burst and leading to sustainable release of compounds for prolong time. Silk coatings on calcium alginate beads provided mechanically stable shells as well as a diffusion barrier to the encapsulated protein drugs thus controlling their release. Scanning electron microscopic observations were carried out to assess cellular viability and biocompatibility of bead embedded-silk 3D scaffolds using fibroblast cells. The results highlight the versatile and tunable properties of calcium alginate embedded fibroin 3D scaffolds making them exciting candidate for the controlled release of a wide spectrum of bioactive molecules from a single delivery vehicle.