To meet the development and application needs of advanced high-strength steel, the laser welding of 22MnB5 hot-forming steel plates with thicknesses of 2 mm, 3 mm, and 4 mm was studied in this paper. Mechanical testing revealed that as plate thickness increased, the tensile strength of welded joints decreased from 1489 MPa to 1357 MPa and 1275 MPa, equating to 96%, 91%, and 88% of the corresponding base metal strength, respectively. The heat-affected zone exhibited the lowest mechanical properties. Microstructural characterization showed that with increasing plate thickness, martensite grains in the welded joints grew larger, transitioning from fine acicular to larger island structures. Concurrently, dislocation density in the welded joints decreased gradually. Furthermore, microstructural changes in the heat-affected zone were more pronounced than those in the fusion zone. The larger grain size and reduced dislocation density softened the joint structure, which consequently decreased the strength and hardness of the welded joint. Laser-welded joints of three thicknesses can exceed 85% of the corresponding base metal strength, demonstrating strong industrial application potential.