This work utilizes in situ transmission electron microscopy–based nanopillar compression to investigate the effect of electrochemical cycling on the mechanical properties of LiCoO2. The ultimate strength of LiCoO2 in the pristine state, and after 1 and 11 cycles are 5.62 ± 0.22 GPa, 3.91 ± 1.22 GPa, and 2.27 ± 1.07 GPa, respectively. The reduced average yield strengths and the large standard deviations of cycled samples, relative to the pristine powder, are hypothesized to result from nonuniform accumulation of Li+ site‐point defects during cycling; either H+ or Li+ vacancies. Density functional theory calculations support our hypothesized link between a nonuniform Li site‐point defect distribution in the cathode and reduction in the materials cohesive strength.