The life prediction of mechanical components in presence of Thermo-Mechanical Fatigue (TMF) is a crucial issue of the design activity. In the combustion engine, that action looks rather difficult because of a superposition of several damage phenomena. Some TMF models are currently available in the literature, but they include many parameters, whose calibration usually requires an onerous testing activity. Therefore, industry requires an assessment of those techniques, to be implemented through some simplified and reliable procedures. In this paper, the prediction of TMF life of a lightweight engine component is based on a new procedure, exploiting the isothermal Low-Cycle Fatigue (LCF) and creep tests, some theoretical approaches applied to TMF and numerical modeling. The A356 Aluminum Alloy is analyzed, as an example of strategic material used to design the new automotive lightweight engines. The calibration of TMF models based on the isothermal LCF and creep tests was found reliable. The fatigue life prediction looks compatible with some preliminary experimental results. Therefore, the proposed approach is suitable to simplify the design procedure, to decrease costs, especially related to testing, and to perform a preliminary trade-off activity of the engine layout.