In this work, the relationship between microstructure and mechanical properties of dissimilar friction stir welded AA6061-to-AA7050 aluminum alloys were evaluated. Experimental results from this study revealed that static strength increased with the tool rotational speed and was correlated with the material intermixing. Fully-reversed low cycle fatigue experimental results showed an increase in the strain hardening properties as well as the number of cycles-to-failure as the tool rotational speed was increased. Furthermore, under both static and cyclic loading, fracture of the joint was dominated by the AA6061 alloy side of the weld. In addition, inspection of the fatigue surfaces revealed that cracks initiated from intermetallic particles located near the surface. In order to determine the corrosion resistance of the dissimilar joint, corrosion defects were produced on the crown surface of the weld by static immersion in 3.5% NaCl for various exposure times. Results revealed localized corrosion damage in the thermo-mechanically affected and heat affected zones. Results demonstrated a decrease in the fatigue life, with evidence of crack initiation at the corrosion defects; however, the fatigue life was nearly independent of the exposure time. This can be attributed to total fatigue life dominated by incubation time. Furthermore, two types of failure were observed: fatigue crack initiation in the AA6061 side at high strain amplitudes (>0.3%); and fatigue crack initiation in the AA7050 side at low strain amplitudes (<0.2%). Lastly, a microstructure-sensitive model based on a multi-stage fatigue damage concept was extended to the dissimilar friction stir welded joints in order to capture the crack initiation and propagation in as-welded and pre-corroded conditions. Good correlation between experimental fatigue results and the model was achieved based on the variation in the initial defect size, microstructure, and mechanical properties of the dissimilar friction stir welded AA6061-to-AA7050 aluminum alloys.