Many high-temperature rotating components are always subjected to complex loading waveforms, arising the concerns for multi-damage driving crack initiation. In this paper, a series of strain-controlled low cycle fatigue (LCF) and creep-fatigue interaction (CFI) tests as well as the novel creep-fatigue combined with high-low cycle (CF-HL) tests were performed in a nickel-based superalloy at 650 ℃. Then, post-test microstructure observations were carried out to reveal the damage mechanisms under the multi-damaged CF-HL loading based on the EBSD-TEM combinative characterizations. In this aspect, the single-slip-dominated deformation mechanism under CFI loadings transformed to double-slip-dominated one under CF-HL loading was revealed. Computationally, a numerical procedure with a combination of crystal plasticity theory and finite element implementation was constructed for predicting the CF-HL crack initiation life and quantifying the crack initiation mechanisms. With the help of the developed fatigue and creep indicator parameters represented by accumulated energy dissipation, good agreements between experimental data and simulated results were achieved within a scatter band of ± 2 on life prediction. In addition, the simulation results indicate that the combined effects of grain orientation and multiple slip system activation showed great influence on the CF-HL crack initiation.