Abstract The fatigue behavior of a Ni-based superalloy GH4169 was investigated using thin tubular specimens under multiaxial loading at 650 °C. Fatigue testing included multiaxial constant amplitude loading and variable amplitude block loading. The test results showed that the characteristics of cyclic hardening or softening depended on the strain loading paths, the sequence of the loading paths, and the loading parameters. Additional hardening due to non-proportional cyclic loading was still present at 650 °C, which caused the fatigue life to decrease. The sequence of the loading paths has an obvious influence on fatigue life, as shown by the increase in loading strain amplitude. Creep effect was observed in the multiaxial fatigue process at high temperature, and an increase in the number of cycles gradually strengthened the creep effect. Fractography showed intergranular fracture phenomena, which reflects the fatigue–creep behavior under non-proportional cyclic loading at high temperature.