The effect of the nucleus on the cell mechanical behavior was investigated based on the dynamic indentation response of cells under a spherical tip. A “two-component” cell model (including cytoplasm and nucleus) is used, and the dynamic indentation behavior is studied by a semiempirical method, which is established based on fitting the numerical simulation results of the quasi-static indentation response of cells. We found that the “ routine analysis ” (based on the Hertz’s contact solution of homogeneous model) significantly overestimated the nucleus effect on the overall cell indentation response due to the effects of the Hertz contact radius and the substrate stiffening. These effects are significantly stronger in the “two-component” cell model than in the homogeneous model. The inaccuracy created by the “ routine analysis ” slightly increases with the modulus ratio of nucleus to cytoplasm and the volume fraction of nucleus. Finally, the error sensitivity to the geometrical parameters used in the model is discussed, which shows the indentation analysis is not very sensitive to these parameters, and the reasonable assumptions for these parameters are effective. This systematic analysis can provide a useful guideline to understanding the mechanical behavior of cells and nuclei.