Cubic-phase AgSbSe2 has been known as a decent p-type thermoelectric material, due to its intrinsically low lattice thermal conductivity; nevertheless, the difficulty in modulating its electrical transport performance impeded its further competition with other state-of-the-art mid-temperature thermoelectrics. In this work, we investigated the effects of Pb doping and Sb vacancies on modulating the thermoelectric properties of AgSbSe2. Pb doping was found to be able to obviously increase the hole concentration, leading to a descending of Fermi level well into the multiple valence bands, thus leading to an enhanced band degeneracy; subsequent Sb vacancies could play the role of relaxing the local lattice strains due to PbSb substitution, resulting in a weakened charge carrier scattering and enhanced weighted mobility. Consequently, a peak power factor PFmax of 7.5 μW cm–1 K–2 at 523 K was achieved in the composition of AgSb0.935Pb0.06Se2, which is 40% higher than that of pristine AgSbSe2. Furthermore, Pb doping and Sb vacancies induce enhanced point defect scattering of high-frequency heat-carrying phonons, yielding a reduced lattice thermal conductivity and a remarkably enhanced maximal ZTmax value of 1.02 at 723 K in the sample AgSb0.935Pb0.06Se2.