Intermittent hypobaric hypoxia (IHH) is critical in osteogenesis and angiogenesis via the HIF-1α and VEGF signaling pathways. However, its specific effect on mandibular bone regeneration remains underexplored. This study aims to evaluate the impact of IHH on the expression of Hypoxia Inducible Factor-1 alpha (HIF-1α), Vascular Endothelial Growth Factor (VEGF), immature bone formation, and changes in mandibular bone microarchitecture. This true experimental study was conducted on 27 male Sprague Dawley rats, randomly divided into three groups: acute bone defect (ABD), bone defect (BD), and hypoxic bone defect (HBD). The HBD group received IHH exposure in a hypobaric chamber simulating 25,000 feet altitude for 5 minutes daily over five consecutive days. HIF-1α and VEGF expression were evaluated using immunohistochemistry. Bone matrix formation was assessed using Masson's Trichrome staining, and bone microarchitecture was analyzed by Micro-Computed Tomography (Micro-CT), including Bone Volume/Total Volume (BV/TV), Bone Surface/Total Volume (BS/TV), Trabecular Thickness (Tb.Th), Trabecular Separation (Tb.Sp), and Trabecular Number (Tb.N). Statistical analysis was conducted using ANOVA and path analysis with a significance level of p < 0.05. Results showed that the HBD group had significantly higher expression of HIF-1α and VEGF (p < 0.05) and increased BV/TV, BS/TV, and Tb.Th, without significant differences in Tb.Sp and Tb.N. These findings demonstrate that IHH enhances osteogenesis and angiogenesis by upregulating HIF-1α and VEGF, improving bone volume and structure. This supports IHH as a promising non-invasive strategy for mandibular bone regeneration, especially in trauma-induced defects. © 2025 Damayanti et al.