Second harmonic generation (SHG) of 2D crystals has been of great interest due to its advantages of phase‐matching and easy integration into nanophotonic devices. However, the polarization‐dependence character of the SHG signal makes it highly troublesome but necessary to match the laser polarization orientation relative to the crystal, thus achieving the maximum polarized SHG intensity. Here, it is demonstrated a polarization‐independent SHG, for the first time, in the van der Waals Nb3SeI7 crystals with a breathing Kagome lattice. The Nb3 triangular clusters and Janus‐structure of each Nb3SeI7 layer are confirmed by the STEM. Nb3SeI7 flake shows a strong SHG response due to its noncentrosymmetric crystal structure. More interestingly, the SHG signals of Nb3SeI7 are independent of the polarization of the excitation light owing to the in‐plane isotropic arrangement of nonlinear active units. This work provides the first layered nonlinear optical crystal with the polarization‐independent SHG effect, providing new possibilities for nonlinear optics. Normally, the SHG signal intensity of nonlinear optical crystals is highly dependent on the angles between polarized light and crystal axis, resulting in big challenges in matching the laser polarization orientation. Hence, the polarization‐independent SHG effect discovered for the first time in layered Kagome Nb3SeI7 crystals is of great significance for nonlinear optics.