Here, we report the fabrication of a curcumin-releasing porous silk fibroin scaffold by simple mixing of fibroin solution (aqueous) with curcumin solution (organic) followed by freeze-thaw of the mixture. The scaffold has a uniform pore distribution with an average pore size of ∼115 μm and a degree of swelling of 2.42% and water uptake capacity of 70.81%. Fibroin showed thermal stability up to ∼280°C, whereas encapsulated curcumin disintegrated at ∼180°C. Fourier transform infrared, powder X-ray diffraction, and nuclear magnetic resonance studies together with UV-visible and fluorescence spectroscopy investigations revealed the solvent (which was used to dissolve curcumin) induced conformational transition of fibroin from silk-I to silk-II that led to the formation of water-stable structure. Fluorescence spectroscopy data also suggested the presence of hydrophobic domains in fibroin and encapsulation of curcumin in such domains through hydrophobic interactions. Release kinetics and mathematical modeling studies indicated a slow and sustained release profile with diffusion as the predominant mode of release. Further, in vitro anticancer, antioxidant, and antimicrobial assays suggested that the biological activity of encapsulated curcumin remains unaltered. The fabrication process is simple, reproducible, and does not require any sophisticated instruments or toxic crosslinking agents. It is anticipated that the curcumin-loaded fibroin scaffold could be used in soft tissue replacements including localized postsurgical chemotherapy against tumors, dressing material for quick healing of wounds and burns, and other related applications. © 2012 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2012.