This article is on the subject of the multiple-fuel cell (MFC) power module system in heavy-duty (HD) electric transportation. The MFC system is promising for increasing the system power level, redundancy, and lifetime and to reduce costs. In particular, the number of FC modules can affect system fluidic and electrical architectures significantly. Furthermore, system complexity and performance can also be influenced. Different MFC system electric architectures can lead to system global efficiency varying a lot, which is closely related to fuel economy. Meanwhile, an optimization strategy can also be used to help assign power demand among FC modules more efficiently, then help reduce power loss and hydrogen consumption. Hence, this article aims to make an investigation of MFC system architecture development in HD electric transportation and find the most suitable architecture from the view of efficiency and fuel economy based on quantitative analysis.