Long-term use of glucocorticoids (GC), especially dexamethasone (Dex), could result in osteoporosis through induction of oxidative stress-mediated apoptosis of osteoblasts and increased differentiation of osteoclasts, finally leading to bone loss. Therefore, searching for new agents that could block Dex-induced cytotoxicity would be a good way to treat osteoporosis. In this study, we show that, synthetic benzo[1,2,5] selenadiazole derivatives (SeDs) could be used as effective inhibitors of Dex-induced osteoblasts apoptosis. This protective effect was correlated with their lipophilicity, cellular uptake and antioxidant activities. Furthermore, mechanistic studies reveal that, treatment of osteoblast cells with Dex resulted in overproduction of intracellular reactive oxygen species (ROS), DNA fragmentation, activation of caspase-3/-9, mitochondria fragmentation, phosphorylation of p53, and activation of MAPKs and AKT pathways. However, pre-treatment of the cells with the synthetic SeDs effectively blocked these intracellular events, which suggest that SeDs could protect osteoblast cells against Dex-induced cell apoptosis via attenuating oxidative stress and downstream signalling pathways. Therefore, this study demonstrates a new therapeutic application of SeDs to antagonize GC-induced osteoporosis.