Cell-substrate interface is known to control the cell response and subsequent cell functions. Among the various biophysical signals, grain structure, which indicates the repeating arrangement of atoms in the material, has also proved to play a role of significant importance in mediating the cell activities. Moreover, refining the grain size through severe plastic deformation is known to provide the processed material with novel mechanical properties. The potential application of such advanced materials as biomedical implants has recently been evaluated by investigating the effect of different substrate grain sizes on a wide variety of cell activities. In this review, recent advances in biomedical applications of severe plastic deformation techniques are highlighted with special attention to the effect of the obtained nano/ultra-fine-grain size on cell-substrate interactions. Various severe plastic deformation techniques used for this purpose are discussed presenting a brief description of the mechanism for each process. The results obtained for each treatment on cell morphology, adhesion, proliferation, and differentiation, as well as the in vivo studies, are discussed. Finally, the advantages and challenges regarding the application of these techniques to produce multifunctional bio-implant materials are addressed.