The development of nanoscience, nanohybrid technology and molecular biology provide an important strategy in the construction of novel bone scaffolds. Nanosized whitlockite (WH) and trace cerium (Ce) element exist widely in human bones; however their positive functions on bone cells/tissues still remain unknown. Inspired by the chemical components and nanostructures of bones, Ce-doped WH/chitosan (Ce-WH/CS) nanohybrid scaffolds were developed for new bone regeneration. The Ce-WH/CS scaffolds exhibited interconnected macropores with sizes of similar to 300 mu m, which facilitated cell adhesion and bone tissue in-growth. Ce-WH nanoparticles with sizes of 10-50 nm were dispersed on macroporous walls. The WH/CS scaffolds with or without doping Ce3+ ions had non-toxicity to human adipose derived stromal cell (hADSCs). Interestingly, the Ce3+ ions in the Ce-WH/CS scaffolds significantly improved osteogenic activity via activated SMAD signaling pathway, and up-regulated the expression of osteogenic-related genes including osteocalcin (OCN), osterix (OSX) and collagen 1A1 (COL1A1). Rat cranial defect models further demonstrated that Ce-WH/CS scaffolds remarkably accelerated material biodegradation and bone tissue growth compared to WH/CS scaffolds. The exciting finding revealed the positive functions of Ce-WH nanoparticles on bone tissues, and provided a promising platform for new bone regeneration.