We report here a high thermoelectric performance in cadmium doped Sb₂Si₂Te₆. The substitution of Ca²⁺ for Sb³⁺ provides a synergetic effect on the electrical transport properties, including hole concentration enhancement, valence band maximum flatting, band gap increase, and density of states effective mass enhancement in Sb₂Si₂Te₆. Such effect leads to the highest power factor of 13.5 μW m^–1 K^–2 at 573 K and average power factor of 12.6 μW m^–1 K^–2 for Sb_1.97Ca_0.03Si₂Te₆. Such enhanced power factor and average power factor are ∼30% and ∼26% higher than that of pristine Sb₂Si₂Te₆ respectively, which is very necessary for the output power optimization of Sb₂Si₂Te₆. In addition, Ca doping also induces extra point defects phonon scattering, leading to a lowest lattice thermal conductivity of ∼0.41 W m^–1 K^–1 at 823 K for Sb_1.99Ca_0.01Si₂Te₆, ∼15% lower than that of pristine Sb₂Si₂Te₆. The simultaneous optimization in power factor and lattice thermal conductivity enables us to achieve a high peak thermoelectric figure of merit ZT of ∼1.3 at 823 K and a high average ZT of ∼0.8 for Sb_1.99Ca_0.01Si₂Te₆, showing its potential for power generator at medium temperature.