The high-power three-level explosion-proof inverters demand high thermal stability of power devices, and a set of theories and methods is needed to achieve an accurate power-loss calculation of power devices, to establish heat dissipation model, and ultimately to reduce the power loss to improve thermal stability of system. In this paper, the principle of neutral point clamped three-level (NPC3L) inverter is elaborated firstly, and a fourth-order RC equivalent circuit of IGBT is derived, on which basis the power-loss model of IGBT and the optimized maternal power-loss thermal model, using an optimized power-loss algorithm, are established. Secondly, in accordance with the optimized maternal power-loss thermal model, the generic formulas of power-loss calculation are deduced to calculate the power-loss modification values of NPC3L and soft switching three-level (S3L) inverters, which will be the thermal sources during thermal analysis for maternal power-loss thermal models. Finally, the experiment conducted on the 2.1 MW experimental platform shows that S3L inverter has the same excellent output characteristics with NPC3L inverter, reduces the power loss significantly by 213 W in each half-bridge, and decreases the temperature by 10°C, coinciding with the theoretical calculation, which verifies the accuracy of optimized power-loss algorithm and the effectiveness of the improvement.