In this study, single crystal and polycrystal models to investigate the fatigue crack propagation mechanism in pure silver through molecular dynamics (MD). At the same time, a combined validation method at micro and macro levels, including transmission electron microscope (TEM), electron back scatter diffraction (EBSD) and compact tension (CT) specimen fatigue testing, is developed to verify the reliability of simulation models and results. The simulation results show that the initial crack orientation is a key factor affecting crack propagation. When the crack propagates within the crystal, two main crack propagation mechanisms are observed: (1) nano-voids appear at the crack tip, and the crack propagates by continuously aggregating with the nano-voids ahead; (2) the formation of stair-rod dislocations and V-shape stacking faults due to dislocation reactions and slip band movements impedes crack propagation, accompanied by the dislocation reaction of Shockley partial dislocations ([112]) generating Hirth dislocations ([110]). The dislocation reaction is verified through the dislocation analysis of the crack tip area of the CT specimen after fatigue experiment by using TEM. In addition, the results of this study show that the angle between the direction of crack propagation and the grain boundary affects the fatigue crack propagation, e.g. when the angle is small, the crack rapidly propagates along the grain boundary. The orientation distribution function (ODF) results of EBSD can verify that the polycrystalline model containing 30 grains is a reliable model for the MD simulation of behavior of the crack tip of CT specimen. Finally, the Paris law constants of pure silver can be determined as m = 3.72 and log C=-10.77, which has reference value for the fatigue analysis and life prediction of silver components or silver welding pots in engineering.