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Osteoarthritis (OA) is an age-related disorder that affects the joints and causes functional disability. <i>Hericium erinaceus</i> is a large edible mushroom with several known medicinal functions. However, the therapeutic effects of <i>H. erinaceus</i> in OA are unknown. In this study, data from Sprague-Dawley rats with knee OA induced by anterior cruciate ligament transection (ACLT) indicated that <i>H. erinaceus</i> mycelium improves ACLT-induced weight-bearing asymmetry and minimizes pain. ACLT-induced increases in articular cartilage degradation and bone erosion were significantly reduced by treatment with <i>H. erinaceus</i> mycelium. In addition, <i>H. erinaceus</i> mycelium reduced the synthesis of proinflammatory cytokines interleukin-1β and tumor necrosis factor-α in OA cartilage and synovium. <i>H. erinaceus</i> mycelium shows promise as a functional food in the treatment of OA.