Methylglyoxal (MG), a highly reactive dicarbonyl compound, is a major precursor in the formation of advanced glycation end products, which are associated with diabetes-related diseases. Bergenin, an active constituent of plants of the genus Bergenia, exhibits multiple biological activities. This study evaluated the effect of bergenin on osteoclast differentiation and determined its mechanism of action. Bergenin reversed MG-inhibited tartrate-resistant acid phosphatase (TRAP) activity and decreased the bone resorption activity of osteoclasts. Quantitative RT-PCR revealed that bergenin decreased the expression of ERK1, Akt2, MMP-9, and OSTM1 genes in the presence of MG. Bergenin pretreatment yielded significant increases in intracellular calcium concentration, mitochondrial mass, mitochondrial membrane potential, and glyoxalase I reduced by MG. Additionally, bergenin decreased the formation of mitochondrial superoxide induced by MG. Detoxification of MG by bergenin may be a viable treatment for bone disorders in patients with diabetes.