Objective To establish a dexamethasone (Dex)-induced zebrafish model of glucocorticoid induced osteoporosis (GIOP) combined with glucocorticoidinduced hypertension (GIHT), and to validate the model by the systematic evaluation of both the phenotypic manifestations and molecular mechanisms. Methods Zebrafish larvae at 3 or 4 d postfertilization (dpf) were divided randomly into a control group (0.1% dimethyl sulfoxide) and a model group (10 μmol/L Dex). Osteogenic parameters and vessel diameter were assessed at 0, 48, and 96 h postadministration (n= 10). Bone mineralization and density were determined by the total area and sum brightness after Alizarin red staining. Vessel diameter was measured by detecting blood flow in the dorsal aorta. After confirming the optimal administration time, expression levels of bone-formation-related proteins (protein kinase B (Akt), glycogen synthase kinase (GSK)-3β, β-catenin) and angiogenesis-related proteins (AMP-activated protein kinase (AMPK), nuclear factor (NF)-κB) were detected by Western Blot to verify the molecular effectiveness of the model. Results Exposure to Dex for 96 h reduced bone mineralization and density in zebrafish larvae compared with the control group, and statistical analysis identified 4 dpf zebrafish and Dex administration for 96 h as the optimal modeling times for the GIOP model. Blood vessel diameter was significantly decreased in the model group compared with the control group (P<0.05), and the difference became more pronounced with longer administration time and was particularly evident at 4 dpf and treatment for 96 h. Western Blot analysis showed that Dex significantly decreased protein expression levels of Akt, β-catenin, and NF-κB (P<0.05) and significantly increased the expression of GSK-3β and AMPK (P<0.05), suggesting that Dex effectively inhibited bone formation and angiogenesis after 96 hours treatment in 4 dpf zebrafish. Conclusions Treatment of 4 dpf zebrafish larvae with 10 μmol/L Dex rapidly established a reliable zebrafish model of GIOP combined with GIHT, providing an ideal animal model for further studies of the common mechanisms of the two diseases and for screening new drugs.