Dissimilar metal welds (DMWs) are commonly employed in various scenarios including the power plants and petrochemicals sector. However, DMWs have been reported for premature failures because of the stresses generated in the weld region owing to the high variation in the coefficient of thermal expansion (CTE) of the different welded pipes’ materials. To overcome the problem of high CTE difference in the weld region some researchers have demonstrated the use of the interlayers between the welded pipes which gradually varies the CTE. In this paper, dissimilar metal welding of 2.25Cr-1Mo steel (CTE = 12 µm/m˚C) and Alloy 800H (CTE = 14.4 µm/m˚C) materials is studied which have a large difference of 20% between their CTEs. To overcome the effect of the high CTE difference between the 2.25Cr-1Mo steel and Alloy 800H, four interlayer materials are added in the weld region, namely; Inconel 625 (12.8 µm/m˚C)/ Inconel 718 (13 µm/m˚C)/ Inconel 600 (13.3 µm/m˚C)/ and Nimonic-PE16 (13.8 µm/m˚C). This results in the gradual variation of the CTE from 2.25Cr-1Mo steel to Alloy 800H. However, no previous research is reported which studied the effect of the thickness of the interlayers on the distortion generated in the weld/joint. This study employs the finite element (FE) analysis to study the effect of the interlayers’ thicknesses on the distortion developed in the joint. For this purpose, a fully coupled temperature-displacement analysis is used. Furthermore, the FE analysis is conducted under the commonly encountered service conditions in the power and petrochemical sectors, i.e., superheated steam passing through the pipe at a temperature of 454˚C and pressure of 21.55 MPa. To systematically study the effect of the interlayers’ thicknesses, a Taguchi L9 design of experiment (DOE) approach is employed by using the levels of thickness as 40 mm, 70 mm, and 100 mm for each interlayer material. The results of the FE analysis reveals that varying the interlayers’ thicknesses between the 2.25Cr-1Mo steel and Alloy 800H have a significant effect on the distortion produced in the joint. Moreover, optimization analysis revealed that employing the interlayers’ thickness combination of Inconel-625 = 100 mm, Inconel-625 = 40 mm, Inconel-625 = 40 mm, Nimonic = 40 mm lead to minimum distortion of 2.27 mm in the joint.