Objective To establish a dexamethasone (Dex)-induced zebrafish model of glucocorticoid-induced osteoporosis（GIOP） combined with glucocorticoid-induced hypertension（GIHT），and to validate the model through systematical evaluation of both phenotypic manifestations and molecular mechanisms. Methods Zebrafish larvae at 3 or 4 days post-fertilization（dpf）were randomly divided into control group （0.1%DMSO）and model group（10 μmol/L Dex）. Osteogenic parameters and vessel diameter were assessed at 0 h，48 h，and 96 h post-administration（Sample size：n = 10）. Bone mineralization and density were determined by the total area and sum brightness from alizarin red staining. Vessel diameter was measured by detecting blood flow in the zebrafish dorsal aorta（DA）. After confirming the optimal administration time，Western blot was used to detect the expression of bone formation-related proteins（Akt，GSK-3β，β-Catenin） and angiogenesis-related proteins（AMPK，NF-κB） to verify the molecular effectiveness of the model. Results After 96 h of Dex exposure，bone mineralization and density in zebrafish larvae were obviously lower than those in the control group，and the statistical analysis indicated that 4 dpf zebrafish at 96 h of administration was identified as the optimal modeling time for the GIOP model. Zebrafish vessel diameter decreased significantly in the model group compared to the control group（P < 0.05），and the difference became more pronounced with longer administration time，particularly evident at 4 dpf treating 96 h. Western blot analysis showed that Dex significantly decreased the protein expression of Akt，β-Catenin，and NF-κB（P < 0.05），while significantly increasing the expression of GSK-3β and AMPK（P < 0.05），suggesting that Dex effectively inhibited bone formation and angiogenesis after 96 h treatment in 4 dpf zebrafish. Conclusions Using 10 μmol/L Dex to treat 4 dpf zebrafish for 96 h can effectively establish a rapid and reliable zebrafish model of GIOP combined with GIHT，providing an ideal animal model for further exploring the common mechanisms of the two diseases and screening new drugs.