In order to study crankshaft fatigue life of high-speed crank press with reverse sliding block, the force analysis of crank slider mechanism was carried out, the dynamics equations of the mechanism were established by D'Alembert principle, and the first derivative and second derivative of the closed loop vector equations of the mechanism were carried out, and the kinematics equations and the acceleration equations of all crank links were obtained. The kinematic equations and dynamics equations were combined by simultaneous constraint method, and all equations were assembled into a sparse matrix. Dynamic simulation model of mechanism was established by MATLAB/Simulink, the sparse matrix was embedded in the simulation model as Function modular, and the iterative solution was conducted by MATLAB/Simulink. As stamping force was considered, the variation of load with time of pressure crank journal, supporting journal and balance crank journal were calculated quickly and accurately. According to the load spectrum calculated by MATLAB/Simulink, the loads were applied on the crankshaft by Workbench, and the fatigue life analysis was carried out by stress fatigue. The results showed that the crankshaft life met design requirements, and there was no obvious damage when crankshaft experienced 10⁷ stress cycles, and the minimum fatigue safety factor was 1.09. The loads of crank journal is obtained by kinematic parameters, which can actually reflect the relationship between velocity, acceleration and inertia load,and that can provide the important theoretical basis for structural design of crank, crankshaft support structures and dynamic balancing structure and the research on bottom dead center accuracy of high-speed press. The results of fatigue life analysis are closer to reality because of the variation of load is obtained by simulation, and the results provide important reference opinions for practical application of press crankshaft.