Thermoelectric (TE) modules for power generation usually operate under high temperatures and large temperature differences, which inevitably introduce thermal stress in the modules. Suppressing the thermal stress is then one of the important issues for improving the service reliability of TE modules. In the past decades, various approaches have been developed for the design optimization of TE module primarily being focused on the enhancement of conversion efficiency, while the influence of structural factors on the module’s mechanical reliability is often overlooked. In this work, we proposed a multi-objective optimization strategy by using the finite element method to evaluate the structural reliability of a TE module, which integrates the module mounting mode, configurational structure of ceramic substrates, thickness of ceramic substrates and electrodes, cross-sectional shape of TE legs, and gaps between [Formula: see text]- and [Formula: see text]-type legs. As a typical sample, the thermal stress of an 8-pair skutterudite (SKD)-based TE module with the framework dimensions of 20 × 22 × 12 mm3 was well studied under the service conditions. The results reveal that a split structure of ceramic substrates and a pressing mounting mode with 2 MPa pressure on the module’s hot-side can significantly reduce the thermal stress in the module. Meanwhile, increasing the gap distance between [Formula: see text]- and [Formula: see text]-type legs, rounding the square column shaped legs, using thin ceramic substrate and thick electrode also can relieve the thermal stress somewhat. The simulation gives a comprehensive solution to reduce the thermal stress and enhance the module’s service reliability for the practical applications through structure optimization.