Friction stir welding and processing (FSW/FSP) are solid-state techniques widely used for joining and localized microstructure and property modifications. Understanding their effects on microstructure evolution and mechanical properties is critical in high-integrity structural design and material-process optimization. In this study, four aluminum alloys (wrought 6061 and cast A356, 319, and A390) were FSPed using various processing parameters in both as-fabricated and pre-weld heat treated conditions. Weld quality was uniquely characterized for different processing parameters (i.e., combinations of rotational and traverse speeds), and optimized processing domains were identified for each material. Resulting microstructures, hardness/micro-hardness, and tensile properties were systematically evaluated and mechanistically correlated to morphological changes in grain structures, characteristic phases, and strengthening precipitates. An original thermo-mechanical model was also developed to predict the temperature history, internal stresses, and material flow during the FSW process. This model was further used to understand and predict weld quality, microstructure evolution, and mechanical properties.