The control of early inflammatory reactions and recruitment of progenitor cells are critical for subsequent tissue repair and regeneration after biomaterial implantation. The aim of this study was to design a multi-functional biomaterial with a controlled drug delivery system to create an optimal local environment for early osteogenesis. Here, the anti-inflammatory cytokine IL-4 and pro-osteogenic RGD peptide were assembled layer-by-layer on TiO2 nanotubes. A poly(dopamine) (DOP) coating was employed onto TiO2 nanotubes (T/DOP) to functionalized with IL-4 (T/DOP-IL4). Then, a carboxymethyl chitosan hydrogel layer (CG) was generated on T/DOP-IL4 to control IL-4 release and RGD peptide immobilization. Cell co-culture models were applied to study macrophage polarization on various material surfaces and the regulation of mesenchymal stromal cell (MSC) osteogenic differentiation. Our data suggest that T/DOP-IL4/CG-RGD surfaces developed in this study are multi-functional, and can not only drive phenotypic changes in macrophages (switching to anti-inflammatory M2 phenotype), resulting in the production of reparative cytokines such as IL-10, but also enhance MSC differentiation related to the activation of BMP/SMAD/RUNX2 signaling. This study further confirmed that the introduction of anti-inflammatory cytokine (IL-4) and cell adhesive motif (RGD) onto Ti substrate can work synergistically to generate a more favorable early-stage osteo-immune environment with superior osteogenic properties, thus representing a potential ideal surface for the generation of bone biomaterials.