A series of strain-controlled creep-fatigue tests under different loading waveforms are carried out on GH4169 superalloy at 650 °C. In the macroscopic view, a unified viscoplastic constitutive framework is used to describe cyclic deformation process. Particularly, a modified kinematic hardening rule considering loading-dependent effect is developed to simulate the stress relaxation behavior during hold periods. Then, creep-fatigue assessment based on interaction diagram is quantitatively determined by the strain energy density exhaustion (SEDE) approach. In order to elucidate damage mechanisms under various loading conditions, the characterization of damage mechanism is observed from the post-test examination. Main-crack-failure modes from fracture appearance observations and cracking modes from longitudinal sections are studied via scanning electron microscopy (SEM) and electron backscatter diffraction (EBSD), respectively. Furthermore, image-based creep-fatigue diagram is proposed based on metallographic interpretation of mechanisms.