Synovitis of the affected joint is a common in avascular osteonecrosis (AVN). Increased levels of pro-inflammatory cytokine interleukin-6 (IL-6) have been reported in AVN, but the mechanism of this increase remains unclear. Silent information regulator transcript-1 (SIRT1), an NAD-dependent deacetylase, inhibits the release of inflammatory cytokines. Interferon beta (IFN-beta) has clear anti-inflammatory properties. We sought to investigate the effects of IFN-beta treatment on AVN and to evaluate the specific signal pathway relating to IL-6 and SIRT1 affected during AVN. Using a dissection microscope, AVN was surgically induced in the distal femurs of mice. Exogenous IFN-beta was administered to the model mice. The effects of exogenous IFN-beta on AVN model mice were assessed using hematoxylin eosin and safranin-O staining, and bone resorption activity was measured using tartrate-resistant acid phosphatase (TRAP) and CD68 staining. Western blots, real-time RT-PCR, and immunohistochemical staining were performed to evaluate the production of SIRT1 and IL-6 in tissues. The RAW 264.7 cell line and bone marrow derived osteoclasts treated with exogenous IFN-beta. Histological findings indicated well preserved trabecular bone and decreased osteoclast bone resorption activity in IFN-beta treated mice compared with mice in the AVN group. Treatment with IFN-beta increased SIRT1 expression and inhibited secretion of IL-6 in this AVN mouse model. IFN-beta decreased IL-6 secretion by activating SIRT1 in the RAW 264.7 cell and bone marrow derived osteoclasts. Our work suggests that IFN-beta could be used to treat AVN and that both SIRT1 and IL-6 are useful targets for treating patients with AVN.