This article used a combined solution of ABAQUS and FE-SAFE to evaluate the performance and predict the fatigue life of the e-clip (a widely used e-clip in the railway system) under cyclic loading. With the proposed methods, the fatigue life analysis of the e-clip has been performed under 12 working conditions. The results show that the inside of the rear arch has the shortest fatigue life and it is therefore the most critical part, which is proved by the field observation. Another conclusion is that the insertion depth of the rear arch into the cast shoulder (short of the insertion depth) and the clip deflection are two of the most important parameters to the fatigue life. The mismatch of the two parameters may cause e-clip fractures. Finally, after optimization of the fatigue life analysis and energy analysis for the e-clip, it is suggested for the installation of e-clips that the clip deflection should be within 10–12 mm and the gap from rear arch to cast shoulder should be within 3–9 mm.