The present study focuses on three-dimensional two-phase CFD investigation on scaled-up proton exchange membrane fuel cell (PEM-FC) for an active area of 100 cm2 with different designs of serpentine and parallel flow configuration. The humidification of hydrogen and oxygen is varied from 10% to 100% to study the PEM-FC performance. The numerical results of polarization curves predicted in this study have been numerically validated with that of the literature for both parallel and counter serpentine flow channels with active area of 24.8-cm2 PEM-FC. Further upon validation, the numerical study is extended for scaled-up PEM-FC with active area of 100 cm2 with different flow path designs to study its performance characteristics namely polarization curves, species concentration distribution, water content in the membrane electrolyte, and proton conductivity to evaluate the fuel cell performance. The three-dimensional CAD models are created in SOLIDWORKS 10.0 and are discretised hexahedrally using finite volume method. The various governing equations namely conservation of mass, momentum, energy, species concentration, and electrochemical equations are solved numerically with the necessary boundary conditions using the CFD code. The novel design of straight zigzag flow path shows the better performance output over the other designs investigated which is having a higher power density of 0.3711 W/cm2 for 100% relative humidity of reactant and oxidant. © 2019 John Wiley & Sons, Ltd.