The dielectric constant or relative permittivity (εr) of a dielectric material, which describes how the net electric field in the medium is reduced with respect to the external field, is a parameter of critical importance for charging and screening in electronic devices. Such a fundamental material property is intimately related to not only the polarizability of individual atoms but also the specific atomic arrangement in the crystal lattice. In this Letter, we present both experimental and theoretical investigations on the dielectric constant of few-layer In2Se3 nanoflakes grown on mica substrates by van der Waals epitaxy. A nondestructive microwave impedance microscope is employed to simultaneously quantify the number of layers and local electrical properties. The measured εr increases monotonically as a function of the thickness and saturates to the bulk value at around 6–8 quintuple layers. The same trend of layer-dependent dielectric constant is also revealed by first-principles calculations. Our results of the dielectric response, being ubiquitously applicable to layered 2D semiconductors, are expected to be significant for this vibrant research field.