An adaptive operation strategy for on-demand control of DMFC system is proposed as an alternative method to enhance the voltage stability. Based on a single-cell DMFC stack, a newly simplified semi-empirical model is developed from the uniform-designed experimental results to describe the I-V relationship. Integrated with this model, the multi-objective optimization method is utilized to develop an adaptive operation strategy. Although the voltage instability is frequently encountered in unoptimized operations, the voltage deviation is successfully decreased to a required level by adaptive operations with operational adjustments. Moreover, the adaptive operations are also found to be able to extend the range of operating current density or to decrease the voltage deviation according to ones requirements. Numerical simulations are implemented to investigate the underlying mechanisms of the proposed adaptive operation strategy, and experimental adaptive operations are also performed on another DMFC system to validate the adaptive operation strategy. Preliminary experimental study shows a rapid response of DMFC system to the operational adjustment, which further validates the effectiveness and feasibility of the adaptive operation strategy in practical applications. The proposed strategy contributes to a guideline for the better control of output voltage from operating DMFC systems.