Thermomechanical fatigue in distinct crystal orientations of nickel-base single-crystal superalloy was studied. Crack initiation modes and damage mechanisms were characterized on fracture surfaces and longitudinal sections by scanning electron microscope and optical microscope. Creep damage nucleated from casting pores in IP-TMF and propagated under mode I. The creep facets were controlled by the activated slip systems, whereas fatigue damage was orientation-dependent and developed by slipping along different crystallographic planes. Oxidation-assisted cracking in OP-TMF tests was non-crystallographic for all crystal orientations. Multi-layer structures near the crack tip revealed successive growth of oxide and the crack grew within the oxidized material. •Revealed anisotropic TMF life distributions depending on three crystal orientations in a nickel-base single-crystal superalloy.•Confirmed the creep-dominant damage mechanisms of IP-TMF and oxidation-dominant fatigue damage in OP-TMF.•Displayed creep damage initiated from internal casting pores affected by different crystallographic slip systems.•Unveiled surface cracks initiated from oxide spikes under mode I condition in OP TMF, regardless of crystal orientations.