This paper presents a new simulation strategy to be implemented in electromagnetic simulators in order to calculate the level of the induced high-order harmonic components in mono-and bi-layer graphene flakes when they are driven by an input electromagnetic field and to evaluate the frequency response of structures, including graphene. The technique is applied to the design and analysis of a single-stage highorder frequency multiplier capable of generating an output signal in the 220-330-GHz range from an input signal in the 26-40-GHz bands, whose topology is based on a structured graphene sheet enclosed in a waveguide resonant cavity that maximizes the incident electromagnetic field. A prototype was implemented to validate the method, obtaining a good agreement with the simulation results. Furthermore, the prototype was also used to experimentally characterize the performance of the multi-layer graphene sheets. In this case, the developed model is used to calculate the frequency response of the structure, but it is not able to predict the output power since the mathematical model describing the frequency conversion phenomena cannot be extrapolated to the multi-layer graphene. Several configurations were tested in order to determine the influence of the graphene sheet's thickness and shape on the output power. Finally, a −33-dBm level output signal at 280 GHz was generated as the seventh-harmonic component of an input signal with a frequency of 40 GHz, showing that the presented prototype can be used as a signal generator in practical submillimeterwave applications.