Bio-nano interfaces between biological materials and functional nanodevices are of vital importance in relevant energy and information exchange processes, which thus demand an in-depth understanding.One of the critical issues from the application viewpoint is the stability of the bio-nano hybrid under mechanical perturbations. In this work we explore mechanical responses of the interface between lipid bilayer and graphene under hydrostatic pressure or indentation loads. We find that graphene coating provides remarkable resistance to the loads, and the intercalated water layer offers additional protection. These findings are discussed based on molecular dynamics simulation results that elucidate the molecular level mechanisms, which provide a basis for the rational design of bionanotechnologyenabled applications such as biomedical devices and nanotherapeutics. Bio-nano interfaces between biological materials and functional nanodevices are of vital importance in relevant energy and information exchange processes, which thus demand an in-depth understanding. One of the critical issues from the application viewpoint is the stability of the bio-nano hybrid under mechanical perturbations. In this work we explore mechanical responses of the interface between lipid bilayer and graphene under hydrostatic pressure or indentation loads. We find that graphene coating provides remarkable resistance to the loads, and the intercalated water layer offers additional protection. based on molecular dynamics simulation results that elucidate the molecular level mechanisms, which provide a basis for the rational design of bionanotechnology available applications such as biomedical devices and nanotherapeutics.