A new class of γ′-containing Co-based superalloys that are promising for high temperature applications has been investigated under cyclic loading conditions. A series of single crystal variants of these Co-based superalloys have been cyclically loaded above their elastic limit at 750 °C in air to study their behavior in the low cycle regime. Interrupted testing was performed to observe the early stages of fatigue failure. Optical microscopy, scanning electron microscopy, and transmission electron microscopy were used to characterize post-mortem specimens. Fatigue failure occurred due to surface cracks that developed during the early stages of cycling in the aluminide-coated sample gauge sections. Growth of these surface cracks into the substrate was associated with extensive oxidation and intermetallic phase precipitation, which accelerated crack propagation as compared to Ni-based superalloys. These observations suggest that improvements in the oxidation resistance and high temperature strength of γ′-containing Co-based superalloys will enhance their fatigue behavior.