Abstract: In the multi-layer and multi-pass welding of large-sized thick plates, in addition to controlling the residual stress and deformation generated during the welding process by adjusting welding process parameters, the planning of the filling path is also an effective means of control. A thermal elastoplastic finite element model of the multi-layer and multi-pass welding process based on the parabolic contour model was developed. Furthermore, the welding heat source model was verified based on the morphology and temperature data of the melt pool. Finally, by combining numerical simulation and experimental methods, the influence of different weld bead layouts on residual stress and deformation during the welding process was studied. The research results show that in a V-shaped groove featuring four layers and ten weld beads with a substrate angle of 40° on both sides, the residual stress and deformation are minimal when the third layer is welded from the middle to the two sides, and the fourth layer is sequentially welded. Experimental verification shows that the residual stress and deformation variation law of numerical simulation is consistent with the experimental results. The simulated deformation value in the y-direction is 2.951 mm, and the experimental value is 3.019 mm, with a relative error of 2.25%. This research result provides a theoretical basis for predicting and controlling residual stress and deformation generated by welded joints during optimized multi-layer and multi-pass welding of V-shaped grooves.