The laser welding of 22MnB5 unequal-thickness thin sheets often presents challenges such as incomplete fusion, excessive weld pool width affecting mechanical properties, weld sagging, and splashing. These issues stem from the unique characteristics of laser welding, including deep melting depth, small heat affected zone, and fast welding speed. To address this, ABAQUS software was employed to simulate the welding process of two different thickness of steel sheets under different welding conditions. Using the Box-Behnken Design (BBD) experimental method, welding parameters were optimized, and a response surface model for residual stress and deformation post-welding was established. The effects of laser power, welding speed and beam offset on post-welding deformation and residual stress were studied. In this paper, the residual stress and welding deformation of the weldment after welding are systematically analyzed. Finite element analysis shows that when using optimized welding process parameters for welding, the stress distribution of the welded model is relatively uniform, with a maximum stress value of 547 MPa. The high stress smoothly transitions to the low stress, and deformation occurs at the starting and ending positions of the welding. Experimental results demonstrated that under the optimized parameters, by characterizing the grain structure after laser welding using EBSD, the weld metal exhibits significant fine grain structure and random grain orientation distribution, indicating rapid solidification and crystal growth. In contrast, the grains in the heat affected zone (HAZ) are larger and have a more ordered orientation. The KAM diagram reveals that the strain in the weld metal is higher, the grain interface has a higher dislocation density, and the HAZ dislocation density is lower. EBSD data shows that the grain size of welded joints varies greatly, with an average size of 3.00 µm. There are numerous low angle grain boundaries, joint appearance was enhanced, with no weld sag, bubbles, or splashes. In addition, the yield strength and tensile strength of welded sheet, whether pre-quenching or post-quenching, exhibit good mechanical properties of the welded parts, play an important role in the light-weight work of the automobile.