The development of advanced layered Ni-rich cathodes is crucial for high-energy lithium-ion batteries (LIBs). However, Ni-rich cathodes often suffer from chemomechanical and thermal instabilities, limiting their cycle life. To address these issues, the authors introduce an efficient approach combining single-crystalline (SC) design with in situ high-entropy (HE) doping to create an ultrahigh-Ni cobalt-free layered cathode, LiNi0.88Mn0.09Mg0.03Fe0.03Ti0.02Mo0.00Nb0.01O2 (denoted as HE-SC-N88). This cathode features a grain-boundary-free and stabilized structure with minimal lattice strain, preventing mechanical degradation, reducing surface parasitic reactions, and mitigating oxygen loss. The HE-SC-N88 cathode demonstrates exceptional electrochemical properties, including prolonged cycling stability under strenuous conditions and delayed O loss-induced phase transitions upon heating. The design of HE doping in redefining the ultrahigh-Ni Co-free SC cathodes represents a significant step toward the industrial application of next-generation LIBs.The development of advanced layered Ni-rich cathodes is crucial for high-energy lithium-ion batteries (LIBs). However, Ni-rich cathodes often suffer from chemomechanical and thermal instabilities, limiting their cycle life. To address these issues, the authors introduce an efficient approach combining single-crystalline (SC) design with in situ high-entropy (HE) doping to create an ultrahigh-Ni cobalt-free layered cathode, LiNi0.88Mn0.09Mg0.03Fe0.03Ti0.02Mo0.00Nb0.01O2 (denoted as HE-SC-N88). This cathode features a grain-boundary-free and stabilized structure with minimal lattice strain, preventing mechanical degradation, reducing surface parasitic reactions, and mitigating oxygen loss. The HE-SC-N88 cathode demonstrates exceptional electrochemical properties, including prolonged cycling stability under strenuous conditions and delayed O loss-induced phase transitions upon heating. The design of HE doping in redefining the ultrahigh-Ni Co-free SC cathodes represents a significant step toward the industrial application of next-generation LIBs.