Numerous bioactive molecules produced in cells are involved in the process of bone formation. We consider that appropriate, simultaneous application of two types of bioactive molecules would accelerate the regeneration of tissues and organs. Therefore, we combined aspirin‐loaded liposomes (Asp@Lipo) and bone forming peptide‐1 (BFP‐1) on three dimensional‐printed polycaprolactone (PCL) scaffold and determined whether this system improved bone regeneration outcomes. in vitro experiments indicated that Asp@Lipo/BFP‐1at a 3:7 ratio was the best option for enhancing the osteogenic efficiency of human mesenchymal stem cells (hMSCs). This was confirmed in an in vivo cranial defect animal model. In addition, RNA‐Seq was applied for preliminarily exploration of the mechanism of action of this composite scaffold system, and the results suggested that it mainly improved bone regeneration via the PI3K/AKT signaling pathway. This approach will have potential for application in bone tissue engineering and regenerative medicine.