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An injectable hydroxypropyl-β-cyclodextrin (HPβCD) cross-linking of gelatin (Gel) based hydrogel was embedded with BMSC in vivo bone regeneration of femoral head necrosis. This HPβCD-Gel hydrogel possesses quick gelation within 6 min; a high-water uptake resulted in faster biodegradation, high swelling, and a 3D porous network that strengthened its mechanical, surface, and morphological properties. The results indicated that BMSC showed high cell viability (>90%) during measurement; HPβCD-Gel hydrogels induced BMSC differentiation into osteocytes within 14 days more efficiently than the osteogenic medium. The HPβCD-Gel/BMSC hydrogels that were injected into the necrosis site of the femoral head in the vessels were measured for 2 weeks. In addition, the vessel density and mean vessel diameters increased in the next 2-8 weeks followed by increased new bone formation, according to the in vivo analysis. Overall, our findings show that this method is a promising strategy for improving femoral head necrosis bone regeneration. Injectable HPβCD-Gel hydrogels were successfully developed with controllable gelation time; high water uptake resulted in faster biodegradation, high swelling, and a 3D porous network that strengthened its tunable mechanical properties. BMSC loaded HPβCD-Gel hydrogel composites could promote low cytotoxicity as compared with the HPβCD-Gel hydrogels. Immunohistochemical analysis showed that osteogenic differentiation-related genes including OCN, OPN, and ALP in HPβCD-Gel hydrogels were significantly upregulated after induction by BMSC compared to HPβCD-Gel hydrogels in normal medium. Our innovative HPβCD-Gel/BMSC hydrogels made possible superior osteogenic and femoral head necrosis bone regeneration. [Display omitted] • An injectable HPβCD cross-linking of Gel based HPβCD-Gel hydrogel was fabricated. • 3D HPβCD-Gel hydrogels were confirmed by UV–vis, FTIR, XRD, and SEM analysis. • HPβCD-Gel exhibited a quick gelation, high-water uptake, swelling and degradation. • The injected HPβCD-Gel with BMSC boosted bone regeneration in osteonecrosis. • HPβCD-Gel/BMSC improved morphological and histological outcomes. [ABSTRACT FROM AUTHOR]