The immune response induced by surface topography crucially determines the implant success. However, how the immune response is mediated by the size of surface topography remains unclear. Hence, various biocompatible Mg-Al layered double hydroxides sheet-array films with different sizes (nano, micro and nano/micro mixture) were constructed on the biomedical titanium, and their osteo-immunomodulation effects on the macrophages were explored. The nano-sheet array structures significantly promoted the polarization of M2 macrophages by activating the PI3K-AKT-mTOR signaling pathway with high gene expressions of integrin β2 and FAK. While the micro-sheet array structures enhanced osteogenic differentiation of mouse bone marrow mesenchymal stem cells (mBMSCs) via ROCK-YAP/TAZ-mediated mechanotransduction. Moreover, the nano-sheet array structures promoted the osteogenic differentiation of mBMSCs with a high proportion of M2 macrophages through a shared medium. This study gave further information concerning integrin-induced focal adhesions in cells of different sheet array structures and their role in macrophage polarization and osteogenic differentiation of mBMSCs, which might help to design biomaterial surfaces with optimal geometry for a desired immunemodulation.