High-mobility group box chromosomal protein (HMGB-1) contributes to osteoarthritis (OA) by modulating various oxidative, inflammatory and apoptotic signaling pathways. The effect of chrysin (CH), a natural plant flavonoid, and its functional interaction with HMGB-1, was investigated in a chondrocyte model of OA. Human chondrocytes were pre-treated with CH, and then subsequently treated with IL-1β to induce the formation of chondrocytes similar to those found in OA joints. Next, the expression level of HMGB-1 was determined by immunofluorescence and western blot analysis. Additionally, inflammatory factor expression was measured by ELISA, and cell apoptosis was analyzed with flow cytometry. To further explore the effects of CH, HMGB-1 expression was silenced following CH treatment with small interfering (si)RNA. The results demonstrated that CH inhibited cell apoptosis, dose-dependently reduced matrix metalloproteinase (MMP) 13, collagenase and IL-6 expression, and increased collagen α-1 (II) chain (COL2A1) expression in human osteoarthritis chondrocytes. These effects of CH were accompanied by decreased HMGB-1 expression. Additionally, the expression of MMP13, collagenase, IL-6 and COL2A1, as well as apoptosis, was significantly reduced by HMGB-1 siRNA. These results demonstrated that HMGB-1 is critical for the protective effect of CH on human osteoarthritis chondrocytes, including cell apoptosis and inflammatory factor inhibition, which suggests that CH may have potential therapeutic effect in treating OA by protecting human osteoarthritis chondrocytes via HMGB1 suppression.