An adaptive operation strategy for on-demand control of active direct methanol fuel cells (DMFCs) is proposed as an alternative method to enhance the voltage stability. A simplified semi-empirical model is firstly developed to describe I-V relationships based on uniform-designed experiments. It is then embedded into multi-objective optimizations to construct the adaptive operation strategy. Experimental studies are implemented on different DMFC systems to validate the proposed semi-empirical model, control strategy and system response to operational adjustments. Numerical simulations are also performed to investigate the underlying mechanisms of the proposed adaptive operation strategy. The results show that the adaptive operation strategy provides possibilities for voltage stability enhancement without the sacrifice of energy conversion efficiency. 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. Moreover, the response of DMFCs to operational adjustments is quick, 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.