An extensive experimental and computational investigation of the fatigue behavior of friction stir welding (FSW) of aluminum–lithium alloy (AA2099) is presented. In this study, friction stir butt welds were created by joining AA2099 using two different welding parameter sets. After FSW, microstructure characterization was carried out using microhardness testing, scanning electron microscopy, and transmission electron microscopy techniques. In particular, the metastable strengthening precipitates T₁ (Al₂CuLi) and δ’(Al₃Li) seen in the base metal were observed to coarsen and dissolve due to the FSW process. In order to evaluate the static and fatigue behavior of the FSW of the AA2099, monotonic tensile and fully-reversed strain-controlled fatigue testing were performed. Mechanical testing of the FSW specimens found a decrease in the ultimate tensile strength and fatigue life compared to the base metal. While the process parameters had an effect on the monotonic properties, no significant difference was observed in the number of cycles to failure between the FSW parameters explored in this study. Furthermore, post-mortem fractography analysis of the FSW specimens displayed crack deflection, transgranular fracture, and delamination failure features commonly observed in other parent Al–Li alloys. Lastly, a microstructurally-sensitive fatigue model was used to elucidate the influence of the FSW process on fatigue life based on variations in grain size, microhardness, and particle size in the AA2099 FSW.