The previously developed gelatin/silk fibroin microspheres were loaded with curcumin and applied for anti-inflammatory treatment in monosodium iodoacetate (MIA)-induced osteoarthritis (OA) in a rat model. The MIA-induced OA rats received a single intra-articular injection with gelatin or gelatin/silk fibroin (30/70) microspheres encapsulating curcumin. The therapeutic effects of treatment groups [concentration of interleukin-6 (IL-6) in blood serum, radiographic and the histological grading on articular joint] were compared with those of normal saline treated OA and normal rats. The result showed that both microsphere groups reduced the level of IL-6 in serum after 1 week of treatment. The gelatin/silk fibroin (30/70) microspheres encapsulating curcumin delayed the cellular destruction in articular joint and synovial tissue after 8 weeks. The radiographic and histological gradings on articular cartilage lesion and synovial tissue change of rats treated with gelatin/silk fibroin (30/70) microspheres encapsulating curcumin were close to those of the normal rats. It was explained that the slow-degrading gelatin/silk fibroin (30/70) microspheres released curcumin for extended period and showed a prolonged anti-inflammatory effect, compared to the fast-degrading gelatin microspheres. This delivery system of curcumin was suggested to be applied for localized treatment of anti-inflammatory in OA with minimal invasion.