The interactions between nanoparticles (NPs) and cells are of huge interest because NPs have been extensively researched for biomedical applications. For the cellular entry of NPs, it remains unclear how the cell membrane molecules respond to the exposure of NPs due to a lack of appropriate surface/interface-sensitive techniques to study NP-cell membrane interactions in situ in real time. In this study, sum frequency generation (SFG) vibrational spectroscopy was employed to examine the interactions between lipid bilayers (serving as model mammalian cell membranes) and Au NPs of four different sizes with the same mass, or the same NP number, or the same NP surface area. It was found that lipid flip-flop was induced by Au NPs of all four sizes. Interestingly, the lipid flip-flop rate was found to increase as the Au NP size increased with respect to the same particle number or the same NP surface area. However, the induced lipid flip-flop rate was the same for Au NPs with different sizes with the same mass, which was interpreted by the same "effective surface contact area" between Au NPs and the model cell membrane. We believe that this study provided the first direct observation of the lipid flip-flop induced by the interactions between Au NPs and the model mammalian cell membrane.