We propose a mechanical model that describes the energy dissipation process in the probing of cell adhesion using quartz crystal microbalance with dissipation monitoring (QCM-D). The model considers the QCM-D disk as a harmonic oscillator and the friction between the disk and the cell is modeled as molecular bond rupturing and the fluidic slip at the interface. The bond formation and rupture events are governed by relative motion between the sensor disk and the cell membrane. We consider this interaction as the main energy dissipation channel for the oscillator, as the dynamic molecular bond rupture and the viscous damping of the trapped liquid at the cell/disk interfacial layer contribute to the most energy loss during the harmonic oscillation. The energy loss due to the frictional slip of the stress fiber/cytoplasm is insignificant compared with the bond rupture. At high bond number conditions, the energy dissipation will be dominated by the bond rupture events at the focal adhesion, and bond number and the size of focal adhesion are linearly related to the energy dissipation factors. These findings can serve as an analytical tool for QCM-D based cell adhesion assays.