A general mathematical/numerical methodology was developed for paper-based, microfluidic electrochemical flow cells. The methodology involves capillary flow, imbibition, mass transport, and electrochemical reactions. The combined model was implemented on a novel microfluidic paper-based flow battery called PowerPAD and rendered numerical results that are very close to published experimental data for this prospective flow cell both under steady and unsteady conditions. It also enabled identifying back-diffusion and species crossover as the key factors controlling the power output and runtime of this flow cell while the role of migration flux was shown to be negligible. The mathematical model was also used for optimizing the electrochemical performance of the PowerPAD. By modifying the design of the electrode and the absorbent pad currently used in this particular flow cell, an optimized design was found that is predicted to roughly triple the runtime of the PowerPAD. The new design has a higher efficiency and a flatter power-output curve making it more suitable for small-scale consumer electronics, as compared with the current design. Overall, the research outcomes may contribute to a new generation of practical, biodegradable batteries based on the modified PowerPAD cell design proposed in this work.