Thermo-mechanical fatigue (TMF) tests were carried out for additively manufactured nickel-based superalloy GH4169 with different printing directions. Selective-laser-melting specimens were subjected to a mechanical strain amplitude of 0.8% at temperature 350-650°C, under both in-phase (IP) and out-of-phase (OP) conditions. The research results indicate that the TMF life of horizontally printed samples is significantly longer than that of vertically printed samples. Furthermore, the TMF life under OP conditions is higher than that under IP conditions, with the isothermal fatigue life falling between the two. A crystal plasticity finite element model was established to simulate TMF cyclic deformation, taking into account the influence of plastic dissipation energy. The developed model is able to capture the features of asymmetry of stress-strain responses and initial hardening followed by softening. It was found that the strain distribution pattern is closely correlated with the shear bands generated by crystal slip, and some grains undergo premature softening.