A series of strain-controlled Low-Cycle Fatigue tests (LCF) and Thermo-Mechanical Fatigue tests (TMF) were performed on silicon-molybdenum ductile cast iron SiMo 4.06. LCF tests were performed for various mechanical strain amplitudes at a high strain rate of 3×10−3/s for various temperatures between 20 °C and 750 °C. In addition, several LCF tests were performed for a low strain rate of 1×10−4/s and as fatigue–creep tests with a tensile strain dwell. TMF tests were performed as out-of-phase and fully constrained between 100 °C and 650 °C. The investigation of the damage mechanisms revealed that the predominant failure mode is a combination of graphite-matrix debonding and transgranular crack propagation through ferritic matrix. Finally, a novel damage model based on the dissipated hysteresis energy is proposed in order to effectively predict the lifetime of SiMo 4.06 under LCF and TMF loading. Creep and fatigue damage are each calculated separately and the oxidation effect is taken into account indirectly. Display omitted •LCF and TMF tests were performed for SiMo 4.06 cast iron between 20 °C and 750 °C.•LCF tests were also conducted with a tensile strain dwell and for various strain rates.•Out-of-phase TMF leads to a significantly shorter fatigue life compared to LCF.•Transgranular crack propagation with graphite-matrix debonding is predominant.•The novel damage model incorporates the effect of frequency and mean stress.