By the experiment of the overlap welding of dissimilar materials for the polymethyl methacrylate and 304 stainless steels, the physical phenomena and weld defects during the welding process are analyzed. By the orthogonal tests, the optimized process parameter combination is obtained, and the well-formed weld joints are realized. The influences of the process parameters on the shear stress are analyzed. The study results show that the influences of laser welding speed, pulse width, spot size and pulse frequency on the shear stress are strong, and the maximum shear force of weld joints is 191 N·mm-2. The key factors determining the failure of weld joints are weld defects and energy densities.