This study investigates the microstructural, mechanical, high-cycle fatigue, and fracture behaviour of a dissimilar 2017A-T451/7075-T651 Al alloy joint produced by single-pass friction stir welding (FSW) without post-processing. Residual stress analysis revealed low tensile residual stresses in the longitudinal direction on the crown side and compressive residual stress in the transverse direction and on the root side of the weld, indicating an almost zero-stress state. High-cycle fatigue tests showed the superior fatigue endurance of the FSWed sample due to the synergistic effect of expressive grain refinement and compressive residual stress in the transverse direction. Fractographic observations confirmed a brittle type II failure with low fracture toughness in the base material 7075-T651 alloy. In contrast, both the FSWed samples and the base 2017A-T451 alloy displayed a ductile transition with type I failure, resulting in higher average fracture toughness values. The direction and propagation of the fatigue crack in the FSWed sample were influenced by the microstructure, with the crack completely bypassing the stir region consisting of larger crystal grains that acted as the crack arrester. This study highlights the high potential of single-pass FSW technology for producing thick dissimilar Al alloy joints with enhanced high-cycle fatigue life without requiring post-treatment. The findings of this study can benefit industries that require high-performance lightweight structures with improved fatigue life, such as aerospace and transportation.