Despite the fact that in the mass consciousness nuclear power is associated with increased environmental risks, this type of energy today remains one of the cleanest, most efficient and carbon neutral. Further development of nuclear energy is hampered by the problem of appropriate handling of spent nuclear fuel (SNF). A very attractive concept of the closed nuclear cycle has been developed to solve it. A real-life implementation of this concept requires the development of technological processes for the efficient separation of minor actinides from the rest of the SNF components. Recent progress in this area has been closely associated with N,O-hybrid donor ligands for liquid−liquid extraction. This work systematically reviews the available literature on the topic and provides detailed explanations on the behavior of the most perspective ligands. Notably, another important aspect of the application of N,O-hybrid donor ligands in nuclear cycle analytics through their incorporation in chemical sensors is also discussed.