In this paper, electron beam welding of laser additive manufacturing GH4169 alloy with different crystal orientation difference (0°, 45°, and 90°) were conducted, and the microstructure and mechanical properties of the weld metal under different crystal orientation of the parent metals on both sides were analyzed. The results show that the dendrites of weld structure have obvious preferential orientation, and the weld structure continuously grows based on the base metal crystal. With the increase of the crystal orientation difference (0°, 45°, and 90°), the content of the large-angle grain boundary in the central area of the weld increases first and then decreases; for the fusion line area of the weld, the content of the large-angle grain boundary increases first and then decreases from 0°, 45° and 90°. The tensile test results show that the tensile strength of the welded joint decreases as the crystal orientation difference increases, which are 721.8Mpa, 720.7Mpa, and 702Mpa respectively, and they are all lower than the base metal which has a tensile strength of 737.2MPa. The hardness values of the weld areas with different orientation difference (0°, 45° and 90°) fluctuated slightly at 265 HV. The plastic deformation of the weld metal is affected by the crystal orientation of each region of the weld. It has the same distribution trend as the large-angle grain boundary content. The more soft-oriented crystal content in the structure, the greater the amount of metal structure deformation. The greater the degree of bending, the stronger the plasticity of the welded joint.