The non-bioactivity of titanium can be improved by installing biomolecules on titanium surface. In this regard, mimicking bone extracellular matrix (EMC) can be possible by reproducing integrin and growth factor (GF) signaling. In this work, multifunctional biomimetic peptides containing the well-known RGD motif (or its cyclic analog, cRGD) and a BMP-2-derived peptide (DWIVA or cDWIVA) in a chemically and spatially defined manner were engineered. Such peptides were further used to coat titanium substrates. The successful functionalization of the substrates was assessed by different physicochemical methods. Then, the biological performance of the multifunctional-modified titanium was evaluated. In this regard, the biomimetic peptides were able to enhance MSCs adhesion and osteogenic differentiation in comparison to controls. Moreover, such biomimetic approach was validated in vivo in a model of rat calvarial defect, promoting an improvement of new bone growth and reduced formation of fibrous tissue on functionalized titanium implants.