To realize high quality and high efficiency welding of large thickness titanium alloy, a flux-cored welding wire was developed by optimizing the synergistic mechanism of metal powder cores. The microstructure evolution of the interlayer region of the welded joint was studied, the stress distribution in the process of laser welding was analyzed by numerical simulation, and the ultra-narrow gap laser welding of TC4 titanium alloy plate with 96 mm in thickness was realized. The results show that the average tensile strength of the upper, middle and lower parts of the welded joint is 935 MPa, the average yield strength is 794 MPa, and the elongation is 20%. The average value of the impact toughness of the upper, middle and lower welded joints at room temperature is 31 J, and the microstructure and properties of the welded joints are well distributed along the wall thickness direction. With the pass of welding increasing, the change from compressive stress to tensile stress occurs in the welded seam center; the high stress zone of transversal and longitudinal residual stress is not in the surface of the sample, but in the welded seam with 6 mm to the surface, and the maximum tensile stress is 1030 MPa.