In this study, response surface methodology (RSM) was employed to optimize the welding parameters' effects on mechanical properties of dissimilar welds between Cr-Mo steel grade (P11) and austenitic stainless steel (AISI 316LN). To determine the best welding parameters, variance analysis (ANOVA), desirability function, and perturbation analysis were used to create regression models and identify the significant parameters influencing tensile strength and hardness gaps in the weld joints. The results indicated that welding speed is the most significant parameter affecting both the austenitic hardness gap and tensile strength, while gas flow has the most significant impact on the hardness gap of Cr-Mo steel. Furthermore, welding speed positively influences the mechanical properties of dissimilar weld, whereas welding current has a slight negative effect on tensile strength. The optimum welding parameters were found to be 130 A for welding current, 70 mm/min for welding speed, and 13 l/min for welding gas flow, resulting in hardness gap values of 18.10 HV (Stainless steel side), 27.38 HV (Cr-Mo steel side), and a tensile strength of 453.90 MPa. The optimum parameter effect is concentrated at the weld interfaces between the fusion zone and the heat-affected zone. This effect led to limitations in grain coarsening, a reduction in the martensite and delta ferrite phase percentages, a slight increase in the bainite ratio, and a decrease in carbide precipitations. As a result, a homogenization of strain distribution in the optimum weld was achieved, leading to ductile fracture in Cr-Mo steel.