Fabricating the SbTe(SnTe) compound has been proved as an effective way to suppress the lattice thermal conductivity and optimize the band structure simultaneously for enhancing the thermoelectric (TE) performance of SnTe. In view of the ultra-low carrier mobility resulted from the strong vacancy-electron scattering in SnTe–SbTe alloy, an appropriate weakening of vacancy scattering to pursue ideal compromise among carrier mobility (μ), concentration (n), and density-of-state effective mass (m*) is of great significance for more effective performance promotion. Herein, we propose an approach of cation-site compensation to finely manipulate the transport properties in SbTe(SnTe) alloy. We, for the first time in the SnTe community, contrastively investigated diverse cation-site fillers, including homogeneous atoms (Sn, Pb) and heterogeneous atoms (Cd, Mn) for maintaining high μ with a large m*, which indicated that Mn compensation exhibits the most appealing effect on synergistically modulating the three electrical transport parameters, μ, n and m*. Our study archives a satisfied electrical transport property in the optimized SbTe(SnMnTe) specimen. The atomic structural analysis discovered the coherent Mn-rich nanostructures which will enrich the phonon scattering mechanism while having minimal effect on electron transport. Benefiting from the finely manipulated electron and phonon transports, a peak ZT of ∼1.3 at 773 K and an average ZT of ∼0.78 (300–823 K) are achieved in the SbTe(SnMnTe) alloy. This work provides a feasible strategy to realize the sharply enhanced TE performance in medium-temperature TE system with abundant vacancies.