Fatigue crack propagation in the near-threshold regime was investigated experimentally and numerically in a Ni-based single crystal superalloy, namely, CMSX-4. Fatigue crack propagation tests were conducted at room temperature using four types of specimens with different primary and secondary crystallographic orientations. The results reveal that the crystallographic orientations strongly affect the fatigue crack propagation behavior, including the crack paths, fatigue crack propagation rates, and fatigue threshold. Crystal plasticity finite element analysis was conducted to quantify the slip activity of an octahedral slip system in front of the crack tip, considering the actual 3D geometry of the crack plane and elastic–plastic anisotropy. The fatigue damage parameter, considering the slip activities of the individual octahedral slip systems, provides reasonable explanation for the fatigue crack propagation rates and crack paths in the near-threshold regime, regardless of the crystallographic orientation. Furthermore, these damage parameters are equivalent at the fatigue thresholds for all specimens with different crystallographic orientation.