This study investigates friction stir welding (FSW) in the dissimilar joining process of cladded plates. Samples of 4-mm thick ASTM 572 steel plate cladded with 3-mm thick Inconel®625 represent the base material. In order to limit mixing between the dissimilar materials to keep the corrosion resistance, a two-pass welding procedure was applied. Optimal welding parameters for each pass were identified. The welded specimens were evaluated by light microscopy, SEM equipped with EDS, and mechanical tests such as hardness, bending, and tensile testing. Defect-free joints with excellent surface finish have been obtained with a well-defined interfacial region between both materials. The FSW process changed the microstructure of both metals used in this study to a new refined grain region into the weld with complex microstructure inside the ASTM 572 steel, as well as change from a dendritic to an equiaxial microstructure in the Inconel®625. The breaking and the distribution of the intermetallic and secondary phases of the nickel alloy were promoted by the FSW process, moreover the second welding pass on the Inconel® tempered the steel which had previously been welded in the first FSW weld pass. The mechanical properties within the welding zone increased due to this microstructural rearrangement coupled with the Hall-Petch effect.