The performance and durability of Ni-rich cathode materials are controlled in no small part by their mechanical durability, as chemomechanical breakdown at the nano-scale leads to increased internal resistance and decreased storage capacity. The mechanical degradation is caused by the transient lithium diffusion processes during charge and discharge of layered oxide spherical cathode micro-particles, leading to highly anisotropic incompatible strain fields. Experimental characterisation of the transient mechanisms underlying crack and void formation requires the combination of very high resolution in space (sub-micron) and time (sub-second) domains without charge interruption. The present study is focused on sub-micron focused operando synchrotron X-ray diffraction and in situ Ptycho-Tomographic nano-scale imaging of a single nano-structured LiNi_0.8Co_0.1Mn_0.1O₂ core–shell particle during charge to obtain a thorough understanding of the anisotropic deformation and damage phenomena at a particle level. Preferential grain orientation within the shell of a spherical secondary cathode particle provides improved lithium transport but is also associated with spatially varying anisotropic expansion of the hexagonal unit cell in the c-axis and contraction in the a-axis. These effects were resolved in relation to the grain orientation, and the link established with the nucleation and growth of intergranular cracks and voids that causes electrical isolation of active cathode material. Coupled multi-physics Finite Element Modelling of diffusion and deformation inside a single cathode particle during charge and discharge was validated by comparison with experimental evidence and allowed unequivocal identification of key mechanical drivers underlying Li-ion battery degradation.