Different scales of voids and cavities in karst systems demonstrate considerable potential as exploration targets in the Tarim Basin, northwest China. Numerous diffraction events exist in the seismic data above the karst reservoir in this area because of the strong impedance contrast and irregular shape of voids. The conventional impedance inversion method using migrated data as an input cannot easily estimate the location of voids and the impedance inside the voids. In this case, an alternative approach to impedance inversion that considers the diffractive component of the total wavefield and uses the unmigrated data as an input should be used. The inversion consists of a least-squares minimization of the misfit function between the observed and modeled data. Forward modeling incorporates a combination of reflection and diffraction wavefield components. The adopted method is applied to physical modeling and field data recorded above the karst reservoir. This study’s physical modeling test simulates observed field data and is performed using a high-resolution and high-fidelity 3D modeling system. Inversion results obtained by the proposed and conventional methods are compared. Physical modeling and a field data application show that the adopted impedance inversion method improves the karst location estimation and the acoustic impedance within the voids.