Thermoelectric generators (TEGs) offer a promising solution for harnessing low-grade heat sources including geothermal energy. However, the limited ZT values of current thermoelectric materials and the absence of advanced material-to-system integration technology result in suboptimal performance compared to conventional power generation methods, thereby constraining their large-scale applications in practice. This study has developed a compact TEG, featuring mini-channel liquid–liquid heat exchangers, to simulate low-medium temperature geothermal fluid utilization. The TEG performance was experimentally investigated and the cause of the degradation in module-to-system performance was revealed. The impacts of operational conditions and several beneficial strategies for optimizing thermoelectric performance were systematically analyzed. The results showed that the primary factor contributing to the reduction in module-to-system conversion is attributed to a decrease in internal effective temperature difference, resulting in a 12% decline in open-circuit voltage and a 26% drop in TEG power performance. The implementation of strategies, such as optimizing the flow rate of cooling water, adjusting assembly pressure, and utilizing appropriate thermally conductive pads, resulted in significant increases in net power output by 7.07%, 27.9% and 24.3%, respectively. The economic analysis also suggests that our TEG design can achieve a competitive cost and higher power performance compared to other designs, showcasing its potential for large-scale application in geothermal energy utilization.