As a direct energy converter between heat and electricity, thermoelectric generators (TEGs) have potential applications including recovery of waste heat, and solar thermoelectric power generation. Geometric parameter and material are two critical factors to improve the TEG performance. However, the strategies base on structure design and material development are always separated. There are limited studies on the effects of consolidating them simultaneously. Here, an idea of segmented material coupled with irregularly variable cross-section design was conceived to further improve the TEG output power. The performance of TEGs with rectangular leg, segmented leg, variable cross-sectional leg, and the new design are compared. The coupling effects between various mechanisms are revealed, which are responsible for the superior performance provided by the developed design. Based on this knowledge, a multiparameters optimization was performed through the genetic algorithm to reach the optimal combination of design parameters. The results show that, with a constraint of certain material volume, the optimal performance of the TEG can be further enhanced by coupling segmented material and irregularly variable cross-section design. An improvement of 51.71% was achieved when compared with the conventional counterpart. This work offers a simple route to enhance the TEG performance when the device materials are specified, without an increase in the cost of manufacturing.