In order to further study the effect of welding residual stress on the fatigue strength of a TC4 titanium alloy sheet during laser welding, a laser welding butt joint model for TC4 titanium alloy sheets was established using ABAQUS (2022) software. The temperature and residual stress fields generated during the welding process were comprehensively simulated, and the melt pool shape and residual stress magnitudes were experimentally verified. The experimental parameters included a laser power range of 900–1200 W, welding speeds of 12.5 and 25 mm/s, and a double-sided welding approach with a cooling interval of 20 s between passes. The findings indicate that welding residual stress is primarily concentrated around the weld and the heat-affected zone, predominantly as tensile stress, with the maximum value observed at the weld’s initiation point, reaching 920 MPa—close to the material’s tensile strength limit. Under ideal conditions (without considering welding residual stress), the fatigue life at the weld area is estimated to reach 188,799 cycles, while the fatigue life of the base material without welding is calculated to be 167,109 cycles. However, when accounting for welding residual stress, the fatigue strength of the sheet decreases significantly, with the minimum fatigue life occurring at the weld toe, measured at 10,471 cycles. This study demonstrates that welding residual stress has a substantial impact on the fatigue life of TC4 titanium alloy sheets, particularly in the heat-affected zone, where the fatigue life is reduced by nearly 94% compared to the ideal condition. These results provide critical insights for improving the fatigue performance of laser-welded TC4 titanium alloy components in engineering applications.