Defect engineering is the core strategy for improving thermoelectric properties. Herein, cation doping along with modulation of cation vacancy has been developed in GeTebased materials as an effective method to induce vacancy-based defects to boost their thermoelectric performance. A series of ternary compounds of Ge 9 Sb 2 Te 12−x (x = 0, 0.03, 0.06, 0.09, 0.12, 0.15) was prepared by vacuum-melting and annealing combined with the spark plasma sintering (SPS) process. The role of Sb doping and cation vacancy on thermoelectric properties was systematically investigated. It is found that alloying Sb 2 Te 3 into GeTe increases the concentration of cation vacancies, which is corroborated by both positron annihilation measurements and theoretical calculations. The vacancies, stacking faults, and planar defect interactions determine the thermoelectric transport properties. Adjusting the deficiency of Te effectively tunes the concentration of cation vacancies and dopant defects in the structure. In turn, this tunes the carrier concentration close to its optimum. A high power factor of 32.6 μW cm −1 K −2 is realized for Ge 9 Sb 2 Te 11.91 at 725 K. Moreover, large strains induced by the defect structures, including Sb dopant, vacancy, staking faults, as well as planar defects intensify phonon scattering, leading to a significant decrease in the thermal conductivity from 7.6 W m −1 K −1 for pristine GeTe to 1.18 W m −1 K −1 for Ge 9 Sb 2 Te 11.85 at room temperature. All of the above contribute to a high ZT value of 2.1 achieved for the Ge 9 Sb 2 Te 11.91 sample at 775 K.