In this paper, the influence of process parameters (tool rotational speed, pin design, and configuration of joined alloys) on the macrostructure and mechanical properties of friction stir welded aluminum alloys 7075-T651 and 5083-H111 was characterized. The tool rotational speed and the alloy placement significantly influenced the formation of the weld (especially the stir zone). Superior mixing of materials was obtained at higher rotational speeds and in the configuration with 5083 on the advancing side and 7075 on the retreating side. However, under these conditions, more defects, such as porosity, voids, or wormholes, were found in the stir zone. Regardless of the pin design and weld configuration, with an increasing tool rotational speed, the mechanical properties decrease. Using the Triflute pin, however, guarantees higher tensile strength and weld efficiency (above 100%). The weld configuration did not influence the mechanical properties. The highest tensile strength (371 MPa) defect-free joint was obtained with 5083 on the advancing side, 7075 on the retreating side, a tool rotational speed of 280 rpm, and the Triflute pin.