AbstractThis study addresses a crucial challenge in two‐dimensional (2D) material‐based electronic devices—inefficient heat dissipation across the van der Waals (vdW) interface connecting the 2D material to its three‐dimensional (3D) substrate. The objective is to enhance the interfacial thermal conductance (ITC) of 2D/3D heterostructures without compromising the intrinsic thermal conductivities (κ) of 2D materials. Using 2D‐MoS2/3D‐GaN as an example, a novel strategy to enhance both the ITC across 2D/3D interface and κ of 2D material is proposed by introducing a controlled concentration (ρ) of vacancy defects to substrate's bottom surface. Molecular dynamics simulations demonstrate a notable 2.1‐fold higher ITC of MoS2/GaN at ρ = 4% compared to the no‐defective counterpart, along with an impressive 56% enhancement in κ of MoS2 compared to the conventional upper surface modification approaches. Phonon dynamics analysis attributes the ITC enhancement to increased phonon coupling between MoS2 and GaN, resulting from polarization conversion and hybridization of phonons at the defective surface. Spectral energy density analysis affirms that the improved κ of MoS2 directly results from the proposed strategy, effectively reducing phonon scattering at the interface. This work provides an effective approach for enhancing heat transfer in 2D/3D vdW heterostructures, promisingly advancing electronics’ heat dissipation.