The present study mainly focuses on the different combinations of significant operating parameters like inlet relative humidity of anode gas and cathode gas, operating pressure, and nature of cathode gas on the performance of proton exchange membrane fuel cell using validated 3-D, single-phase, and non-isothermal model with the help of ANSYS FLUENT 18.1 package. The results of different combinations on the performance of proton exchange membrane fuel cell are compared with independent effects of the operating parameters. Results revealed that the combined operating parameters' effect on the performance of the proton exchange membrane fuel cell is deviated significantly (up to 5%) compared to the expected summation of individual parameters effect which is considerable in fuel cell scaling and stack applications. Nature of gas, operating pressure, and inlet cathode gas relative humidity are the most significant parameters in the automobile applications which have to be dealt with care where the combination of changes in operating parameters is quite phenomenal.