This study introduces a step-by-step, summarized overview of direct methanol fuel cell (DMFC) fundamentals, thermodynamic–electrochemical principles, and system evaluation factors. In addition, a parametric investigation of a JENNY 600S DMFC is conducted to simulate cell performance behavior under varying operating conditions. The system is mathematically modeled and solved in MATLAB and accounts for multi-irreversibilities such as the activation and ohmic and concentration overpotentials. The performance of the modeled system was validated against theoretical and experimental results from the literature. The results indicated that increasing the fuel cell’s operating temperature yields enhanced output cell voltages due to enhanced methanol oxidation reactions. Nevertheless, the maximum efficiency limits of the fuel cell tend to decrease with an increase in temperature. In addition, the model has also depicted that enhanced output cell voltages are associated with increased oxygen consumption, resulting in the lower exit flowrates of the reactants.