For a wide-flanged composite box girder bridge, the risk of fatigue cracking in the external inclined strut welded joint under the fatigue vehicle load is a problem. The main purposes of this research are to verify the safety of the main bridge of the Linyi Yellow River Bridge, a continuous composite box girder bridge, and to propose suggestions for optimization. In this research, a finite element model of one segment of the bridge was established to investigate the influence surface of the external inclined strut, and, using the nominal stress method, it was confirmed that the fatigue cracking of the welded details of the external inclined strut was risky. Subsequently, a full-scale fatigue test of the external inclined strut welded joint was carried out, and the crack propagation law and S-N curve of the welded details were obtained. Finally, a parametric analysis was conducted with the three-dimensional refined finite element models. The results showed that the welded joint in the real bridge has a fatigue life larger than that of the design life, and methods such as increasing the flange thickness of the external inclined strut and the diameter of the welding hole are beneficial to improve its fatigue performance.