This article presents an experimental test program and numerical analyses conducted on aluminum alloy drill pipes with two different geometries. Small-scale characterization tests were conducted to determine both the material mechanical properties and the fatigue S–N curves. Full-scale fatigue tests of the components are also presented. A finite element model of the drill pipes, including the tool-joint region, was developed. The model simulates, through different load steps, the tool-joint hot-assembly and the experimental loads to obtain the actual stress distribution during the full-scale tests. Maximum stress amplitude in the aluminum pipes was found to be coincident with the edge of the connector, at the same location where failure was observed in full-scale tests. The study revealed that such pipes present a complex stress state near their connection to the steel tool-joints due to their geometry and the residual stresses induced during the assembly of the steel connectors onto the aluminum pipes. Finally, multi-axial fatigue models were calibrated with the results of the small-scale tests and applied to the stress–strain state obtained numerically. Theoretical predictions were correlated with full-scale fatigue test results.