The ever-increasing demand for electric-vehicle and grid-storage markets necessitates advances in lithium-ion batteries (LIBs) with higher energy density and longer cycling life. Single-crystal nickel (Ni)-rich cathodes (SC-NMCs) have garnered widespread attention in the LIB community, due to their high tap density, mechanical robustness, and boundary-free architecture. While SC-NMC cathodes have shown exceptional stability and performance at low Ni content, they exhibit pronounced capacity degradation and structural instability as Ni content increases beyond 80% or under high-voltage cycling conditions. Furthermore, numerous studies have adopted a trial-and-error approach to modifying SC cathodes, often relying on degradation indicators and modification strategies developed for conventional polycrystalline (PC) NMC cathodes, despite the fundamentally distinct chemo-mechanical degradation pathways of SC materials. This thesis systematically investigates the chemo-mechanical evolution in SC-NMC cathodes to identify the critical factors limiting their performance, to evaluate the compositional effects, and to provide effective guidelines for their optimization and future development. In Chapter 1, we explore the performance gap between PC- and SC-NMC cathodes under high-Ni-content conditions. Multi-scale operando techniques reveal that the degradation in SC-NMC cathodes is primarily driven by internal bulk strain rather than surface reactions. The heterogeneous Ni oxidation in the micron-sized SC particles during cycling generates non-uniform strain distributions and irreversible oxygen redox activity, resulting in intragranular cracking and phase transformation. Therefore, unlike PC cathodes, which demonstrate better chemo-mechanical stability despite more severe surface reconstruction, SC cathodes suffer from poor cycling performance due to more strain-driven microcrack formation within a single particle. These findings highlight the critical role of Ni redox behavior in influencing the mechanical stability and electrochemical performance of Ni-rich cathodes. Building on these insights, Chapter 2 focuses on unraveling the nanoscopic strain evolution in SC-NMC cathodes, challenging traditional composition-driven strategies derived from PC systems. Through a combination of advanced diagnostics and modeling, we reveal that mechanical degradation in SC-NMC is decoupled from lattice volume changes, instead driven by kinetic heterogeneities and multiple-dimension lattice distortions. Our study identifies manganese (Mn) as a major contributor to localized strain accumulation in SC cathodes, exacerbating structural degradation, while cobalt (Co) mitigates these effects by enhancing structural integrity and diffusion pathways. These findings not only redefine the compositional requirements for SC-NMC cathodes, but also emphasize the need for tailored strain modulation strategies distinct from those applied to PC materials. This thesis advances the understanding of chemo-mechanical evolution mechanisms in SC-NMC cathodes, facilitating the refinement of existing strategies and driving innovation in cathode design. By bridging the gap between degradation behaviors and material design, this work offers a comprehensive framework to guide the future improvement of SC-NMC cathodes, paving the way for next-generation LIBs with improved longevity and performance.