Friction stir welding is a solid-state welding technique for joining metals such as aluminum alloys quickly and reliably. This article presents a design of experiments approach (central composite face–centered factorial design) for predicting and optimizing the process parameters of dissimilar friction stir welded AA6351–AA5083. Three weld parameters that influence weld quality were considered, namely, tool shoulder profile (flat grooved, partial impeller and full impeller), rotational speed and welding speed. Experimental results detailing the variation of the ultimate tensile strength as a function of the friction stir welding process parameters are presented and analyzed. An empirical model that relates the friction stir welding process parameters and the ultimate tensile strength was obtained by utilizing a design of experiments technique. The models developed were validated by an analysis of variance. In general, the full impeller shoulder profile displayed the best mechanical properties when compared to the other profiles. Electron backscatter diffraction maps were used to correlate the metallurgical properties of the dissimilar joints with the joint mechanical properties as obtained experimentally and subsequently modeled. The optimal friction stir welding process parameters, to maximize ultimate tensile strength, are identified and reported.