Bone tissue engineering provides a promising strategy for the treatment of bone defects. Nonetheless, the clinical utilization of biomaterial-based scaffolds is constrained by their inadequate mechanical strength and absence of osteo-inductive properties. Here, we proposed to endow nano-scaffold (NS) constructed by coaxial electrospinning technique with enhanced osteogenic bioactivities and mechanical properties by incorporating biocompatible magnetic iron oxide nanoparticles (IONPs) and icaritin (ICA). Four types of nano-scaffolds (NS, ICA@NS, NS-IONPs and ICA@NS-IONPs) were prepared. The incorporation of ICA and IONPs minimally impact their surface morphological and chemical properties. IONPs enhanced the mechanical properties of NS scaffolds, including hardness, tensile strength, and elastic modulus. In vitro assessments demonstrated that ICA@NS-IONPs exhibited enhanced osteogenic bioactivities towards mouse calvarial pre-osteoblast cell line MC3T3-E1 as evidenced by detecting the alkaline phosphatase (ALP) activity level, expressions of osteogenesis-related genes and proteins as well as mineralized nodule formation. Mechanistic investigations revealed that MEK/ERK (MAP kinase-ERK kinase (MEK)/extracellular-signal-regulated kinase (ERK)) signaling pathway could offer a plausible explanation for the osteogenic differentiation of MC3T3-E1 cells induced by ICA@NS-IONPs. Furthermore, the implantation of nano-scaffolds in rat skull defects exhibited a substantial improvement in in vivo bone regeneration. Therefore, IONPs and ICA incorporated coaxial electrospinning nano-scaffolds present a novel strategy for the optimization of scaffolds for bone tissue engineering.