Substrate is crucial to develop nanocalorimeter with high performance. By analysis on theory of microelectro-mechanical system（ MEMS） nanocalorimeter and thermal loss using finite element analysis（ FEA） effect of different types of substrate materials and structure on thermal distribution and power consumption are studied and the feasibility of the device is verified by simulation of nanocalorimetric signals. Characteristics of the device is optimized according to the simulation results. The research can provide reference basis for design and simulation of other type of nanocalorimeter.