Automotive exhaust manifolds are continuously exposed to severe thermo-mechanical cycling, which promotes crack initiation and growth in regions of high stress concentration. The present study investigates the influence of material selection on the fatigue life prediction of exhaust manifolds through a finite element analysis combined with a strain-based fatigue criterion. Two stainless steels, AISI 304L and AISI 321, are considered due to their wide industrial use and distinct microstructural stability at elevated temperatures. A thermo-mechanical finite element model was developed to simulate realistic operating conditions, including temperature gradients, mechanical constraints, and material nonlinearity. Fatigue life estimation was performed using the Smith–Watson–Topper parameter, which accounts for both the maximum stress and strain amplitude in each cycle. This approach provides a reliable indicator of crack initiation under multiaxial thermo-mechanical loading. The comparative results highlight the significant role of material properties in fatigue resistance. The titanium stabilization of AISI 321 enhances oxidation and creep resistance, leading to delayed crack initiation and improved durability compared to AISI 304L. The study confirms that accurate fatigue modeling coupled with appropriate material selection contributes to the robust design of high-temperature automotive components.