In deep-water test conditions, the riser-test pipe system (RTS) is subject to the vortex induced effect on riser, flow induced effect on test pipe and longitudinal/transverse coupling effect, which is prone to buckling deformation, fatigue fracture and friction perforation. To resolve this, the three-dimensional (3D) nonlinear vibration model of deep-water RTS is established using the micro-finite method, energy method and Hamilton variational principle. Based on the elastic-plastic contact collision theory, the nonlinear contact load calculation method between riser and test pipe is proposed. Compared with experimental measurement results, calculation results of the proposed vibration model in this study and the single tubing vibration model in our recent work, the correctness and effectiveness of the proposed vibration model of the deep-water RTS are verified. Meanwhile, the cumulative damage theory is used to establish the fatigue life prediction method of test pipe. Based on that, the influences of outflow velocity, internal flow velocity, significant wave height, as well as top tension coefficient on the fatigue life of test pipe are systematically analyzed. The results demonstrate that, first, with the increase of outflow velocity, the maximum alternating stress, the annual fatigue damage rate increased and the service life decreased significantly. The locations where fatigue failure of the test tube is easy to occur are mainly distributed at the upper “one third” and the bottom of test pipe. Second, with the increase of internal flow velocity, the “one third effect” of the test pipe will decrease, and is shown “the bottom damage effect”, which needs the attention of field operators. Third, during field operation, it is necessary to properly configure the top tension coefficient so that there can be a certain relaxation between the riser and the test pipe, so as to cause transverse vibration and consume some axial energy and load. The study led to the formulation of a theoretical method for safety evaluation and a practical approach for effectively improving the fatigue life of deep-water test pipe.