BACKGROUND: Bone defects, particularly in the mandible, pose significant clinical challenges due to the limited regenerative capacity. Effective bone tissue engineering requires biomaterials that promote both osteogenesis and angiogenesis. This study developed an optimized collagen-nano hydroxyapatite scaffold loaded with dexamethasone and stem cells to enhance bone regeneration. METHODS: The scaffold was fabricated using the freeze-dryer method. Characterization was performed using Fourier Transform Infrared Spectroscopy (FTIR), energy-dispersive X-ray (EDX) analysis, and scanning electron microscopy (SEM). Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs) were incorporated into the scaffold, and in vitro and in vivo assessments were conducted. RESULTS: FTIR and EDX analyses confirmed the successful incorporation of nano-hydroxyapatite and dexamethasone. SEM revealed an interconnected porous structure with an average pore size of 28.55 µm. The scaffold loaded with WJ-MSCs significantly enhanced osteocyte and osteoblast populations, leading to improved mandibular bone formation. Histopathological evaluations demonstrated superior osteogenesis and angiogenesis. CONCLUSION: The developed porous nanohybrid scaffold shows potential as a promising biomaterial for bone tissue engineering applications.