Thermal fatigue experiments were performed on a single-edge wedge specimen of Ni-resist D5S cast iron to reproduce the conditions to which exhaust manifolds are subjected during service. The leading edge temperature was cycled between 20°C and 850°C, and the temperature distribution on the specimen surface was measured with thermocouples during thermal cycling. Due to the complexity of the loads, a uncoupled thermomechanical computation of the problem was performed using the three-dimensional finite element code ABAQUS to evaluate the temperature, stress and strain distribution over a thermal fatigue specimen. The heat fluxes and forced convection coefficients generated by the thermal fatigue benchmark were optimized in both heating and cooling phases by reverse engineering to reproduce the experimental temperature-time profiles measured by thermocouples on the surface of the specimen. Then, an elastic-viscoplastic tow-layer model was used to simulate the mechanical behavior of the studied material. It was found that the maximum stress value was located in the center of the specimen at the edge of the wedge. This result was confirmed by experimental observations. The crack initiation zone is located in the edge zone and the direction of crack propagation is perpendicular to the edge line toward the thick part of the specimen. The saturation of the main crack propagation near the uniform specimen zone was mainly explained by the rapid decrease of the energy dissipated per cycle.