Abstract: Objective The hybrid structure of stainless steel/nickel-based alloy with different thickness has wide application prospects in the aviation, aerospace, and power industries. It is of great significance to carry out study on laser welding process of stainless steel and nickel-based alloys. Methods 304 stainless steel and Inconel 718 nickel-based alloy materials are connected by laser welding technology. Influence of welding speed and beam offset on weld formation, microstructure and tensile strength of welded joints is compared and analyzed. Results The results show that when welding power is 3 kW and laser focus shifts to stainless steel by 0.2 mm, curvature radius increases first and then decreases as welding speed increases. Among them, weld formability is the best when welding speed is 1.5～2.0 m/min. The overall formability when laser beam is focused on the stainless steel side is better than that on the nickel-based alloy side. Conclusion When laser position is offset on the nickel-based alloy side, tensile strength of welded joints is generally higher, the maximum tensile strength is 647 MPa. Finally, through observing location of fracture, it is found that most of fractures are on the nickel-based alloy side, and fractures are dominated by micro-hole aggregation type plastic fractures. Non-convective mixing zone is observed in microstructure of weld on the stainless steel side, but not on the nickel-based alloy side.