Mori folium, the leaf of Morus alba L. (Moraceae), has been widely used in traditional medicine for the treatment of various diseases. It has been recently reported that Mori folium possesses potential chondroprotective effects in interleukin (IL)‑1β‑stimulated human chondrocytes; however, its protective and therapeutic potential against osteoarthritis (OA) in an animal model remains unclear. In this study, as part of an ongoing screening program to evaluate the anti‑osteoarthritic potential of Mori folium, the protective effects of a water extract of Mori folium (MF) on cartilage degradation and inflammatory responses in a monosodium iodoacetate (MIA)‑induced OA rat model were evaluated. The results demonstrated that administration of MF had a tendency to attenuate the damage to articular cartilage induced by MIA, as determined by knee joint swelling and the histological grade of OA. The elevated levels of matrix metalloproteinases‑13 and two bio‑markers for the diagnosis and progression of OA, such as the cartilage oligomeric matrix protein and C‑telopeptide of type II collagen, were markedly ameliorated by MF administration in MIA‑induced OA rats. In addition, MF significantly suppressed the production of pro‑inflammatory cytokines, including IL‑1β, IL‑6 and tumor necrosis factor‑α. MF also effectively inhibited the expression of inducible nitric oxide (NO) synthase and cyclooxygenase‑2, thus inhibiting the release of NO and prostaglandin E2. Although further work is required to fully understand the critical role and clinical usefulness, these findings indicate that MF may be a potential therapeutic option for the treatment of OA.