The printed circuit board (PCB)-based direct methanol fuel cell (DMFC) package is a novel manufacturing and assembly process, which is full potential in mass production, and very limited literatures make study on the effects of the related process parameters. The hot press is a necessary and key process to make the PCB package, i.e., the key component of a DMFC, membrane electrode assemblies (MEA), needs to sustain a severe test. In order to minimize the process-induced damage of the MEAs, it is important to make a good control on the process parameters. Therefore, the objective of this paper is to present a methodology to explore a good combination of hot-press parameters. The considered parameters include the compression ratio of the MEA, heating time, heating temperature, and hot pressing pressure acting on the MEA. During the experimental investigation, a series of experiments was made first to discuss the effect of the individual parameter of the hot-press process on the MEA performance, wherein a reasonable range of each process parameter condition was able to be well defined. Moreover, the Taguchi experimental method was adopted to explore the parameter effects on the DMFC performance during the digital packaging process and to determine the best combination of parameter conditions. At the end, a MEA was made a hot press under the best parameter combination, which could verify the result obtained from Taguchi’s experiments. The result is able to be an important reference for the future manufacturing design guideline of PCB-based DMFC package.