One of the advantages of friction stir welding process is its ability to join dissimilar metals and alloys. The aim of this work is to predict mechanical properties, i.e., tensile strength, hardness, and elongation of aluminum 6061 to aluminum 5010 joint that is fabricated by friction stir welding process. Here, response surface methodology based on central composite design with three parameters, five levels, and 20 runs was used to conduct experiments and to develop mathematical regression models. The three welding parameters considered were tool rotary speed, welding speed, and plunging depth. Analysis of variance was then performed to check the adequacy of developed models. The effects of process factors on mechanical properties were studied using developed mathematical models and on the basis of macrostructure and microstructure characterization and fractography of joints which are examined by optical and scanning electron microscopy. Finally, optimal parameter setting was identified by performing optimization through desirability approach function.