As an ideal candidate for PbTe, which maintains excellent performance in mid-temperature, PbSe holds great application potential. In this work, based on an optimized dynamic doping material system, a series of entropy-enhanced n-type lead chalcogenides Pb1-ySnySe1-xTexSx-2at%Cu (x=0, y=0；x=0.1, y=0; x=0.25, y=0; x=0.25, y=0.125) are synthesized. The thermoelectric properties of PbSe are modulated by gradually increasing its configurational entropy through alloying with Te/S/Sn. Research results show that the increase in configurational entropy improves the crystal symmetry of PbSe and significantly increases the Seebeck coefficient while maintaining good electrical properties. The dense dislocations, nanoscale to submicron-scale incoherent precipitates generated lead to the localization of phonons, increase anharmonicity, and reduce the lattice thermal conductivity at room temperature to 0.73 W m-1 K-1. The total thermal conductivity drops significantly by 69.8%. Consequently, the thermoelectric properties of Pb0.875Sn0.125Se0.5Te0.25S0.25-2at%Cu are remarkably improved, with a maximum dimensionless merit ZTmax of ~ 1.46 at 623 K and an average dimensionless merit ZTave of ~ 1.15 at 300–700 K. In addition, the room-temperature dimensionless merit ZTRT ~ 0.64 is the highest level reported for n-type PbSe. This optimization strategy of dynamic doping combined with entropy engineering to regulate electron and phonon transport, demonstrates a feasible means to improve thermoelectric performance.