Rocket engine nozzle structures typically fail after a few engine cycles due to the extreme thermomechanical loading near the nozzle throat. In order to obtain an accurate lifetime prediction and to increase the lifetime, a detailed understanding of the thermomechanical behavior and the acting loads is indispensable. The first part is devoted to a thermally coupled simulation (conjugate heat transfer) of a fatigue experiment. The simulation contains a thermal FEM model of the fatigue specimen structure, RANS simulations of nine cooling channel flows and a Flamelet-based RANS simulation of the hot gas flow. A pseudo-transient, implicit Dirichlet–Neumann scheme is utilized for the partitioned coupling. A comparison with the experiment shows a good agreement between the nodal temperatures and their corresponding thermocouple measurements. The second part consists of the lifetime prediction of the fatigue experiment utilizing a sequentially coupled thermomechanical analysis scheme. First, a transient thermal analysis is carried out to obtain the temperature field within the fatigue specimen. Afterwards, the computed temperature serves as input for a series of quasi-static mechanical analyses, in which a viscoplastic damage model is utilized. The evolution and progression of the damage variable within the regions of interest are thoroughly discussed. A comparison between simulation and experiment shows that the results are in good agreement. The crucial failure mode (doghouse effect) is captured very well.