Microstructure inhomogeneity and through-thickness creep properties of friction stir welding (FSW) 7B50-T7451 aluminum alloy thick plate joint were investigated. The results show that creep properties of the FSW joint deteriorate along the thickness direction from the top to the bottom. Both the grain size and fraction of the low-angle grain boundaries (LAGBs) in the weld nugget zone (WNZ) decrease from the top to bottom. A larger volume of precipitate free zone (PFZ) and coarser precipitates in the bottom slice reduce creep resistance compared with the top. The precipitates in the heat-affected zone (HAZ) exhibit continuous coarsening with the increase of creep temperature, inducing the decrease of threshold stress. The dominant creep mechanism transforms from dislocation creep in the HAZ to grain boundary sliding (GBS) in the WNZ when creep temperature increases. The fracture mode also changes from transgranular to intergranular fracture.