The state-of-the-art of MEMS-based fuel cell can not meet the requirements of on-chip power application owing to low cell voltage and poor power density. This is mainly resulted from poor process compatibility between traditional fuel cell technology and MEMS industry. In particular, graphite-based porous electrode is difficult to be integrated into MEMS-based fuel cell so that there is lack of enough reaction interfaces. We successfully employed nanoimprint technology to modify proton exchange membrane instead of porous electrode for achieving large reaction interfaces in MEMS-based fuel cell. Novel MEMS-based direct methanol fuel cell (DMFC) was successfully fabricated in this work. The novel MEMS-based DMFC had the open circuit voltage (OCV) and the maximum power density (MPD) higher by about 5.7 and 10 times than the state-of-the-art of MEMS-based DMFC in the literatures, respectively. The novel method enables MEMS-based fuel cell more compact, thinner, higher performance and lower cost for the on-chip power application.