In this research, the thermomechanical fatigue (TMF) characteristics of a second-generation Ni-based single-crystal superalloy were investigated. The combined effects of temperature cycling and mechanical stress were examined using a strain-controlled approach under different TMF testing conditions. The results indicated that cyclic softening occurred during the early stages during in-phase (IP) loading. In contrast, out-of-phase (OP) tests exhibited cyclic hardening, as evidenced by an increase in the stress range, which intensified at higher mechanical strain amplitudes. This resulted in a shorter fatigue life compared to the IP TMF case. The crack distribution patterns and damage mechanisms on the cross-sectional and fracture surfaces of the failed specimens were analyzed. In the OP TMF tests, oxidation-assisted cracking was identified as the primary damage mechanism. The dominance of oxide layers was a key distinguishing feature. Additionally, twinning-related deformation and topologically close-packed (TCP) phase particles were observed in specimens subjected to a higher mechanical strain of 0.6%, where they ran parallel to the main crack, contributing to a reduction in lifetime. Conversely, the IP TMF cases were mainly dominated by creep damage mechanisms, with some signs of oxidation penetration observed during testing. The application of the Ostergren model to the fatigue life prediction of a Ni-based single-crystal superalloy under both conditions was evaluated. As this model was insufficient, a modified Ostergren model was proposed by incorporating the maximum and amplitude stresses in the power law forms.