Macrophages are involved in all phases of scaffold induced tissue regeneration, orchestrating the transition from an inflammatory to regenerative phenotype to guide all other cell types to complete the wound healing process when a tissue defect advances beyond the critical size. Therefore, harnessing macrophages by scaffolds is important for facilitating tissue regeneration in situ. In this work we utilized the superparamagnetic scaffold upon magnetization as a mechanostimulation platform to apply forces directly to macrophages grown in the scaffold, aiming to figure out whether the functions of macrophages related to bone tissue regeneration can be mechanomodulated and to elucidate the underlying mechanisms. We showed the first evidence that upon magnetization the interaction of superparamagnetic scaffolds to macrophages drove them to polarize towards an M2-like phenotype by inhibiting TLR2/4 activation and enhancing VEGFR2 activation, thereby inhibiting secretion of the pro-inflammatory cytokines IL-1β, TNF-α and MCP-1, as well as the osteoclast differentiation cytokines MMP-9 and TRAP, and up-regulating VEGF and PDGF. The conditioned media enhanced the osteogenesis of osteoblasts and the angiogenesis of endothelial cells.