ABSTRACT Strategic fluorination of solvent, a prominent strategy to enhance the electrolyte oxidation resistance and engineer a robust cathode–electrolyte interface, is crucial for realizing high‐voltage lithium‐ion batteries. Actually, the adaptability of fluorinated solvents to high voltages is critically determined by the degree of fluorination and the fluorination site, yet lacks systematic design principles. Herein, we introduce a solvent screening descriptor based on ionization energy and Fukui function to assess molecular and site‐specific reactivity. Computational and experimental results demonstrate that an optimal solvent with low ground‐state energies and reactive sites is required as an ideal candidate for high‐voltage electrolytes. Among derivatives from anisole, (trifluoromethoxy)benzene is identified as a superior candidate, enabling the formulation of a low reactivity solution (LPT) as electrolyte. Remarkably, the prepared Li‖LCO cell using LPT electrolyte maintained a high‐capacity retention of 78.8% after 600 cycles at 4.5 V. In addition, the formation of an inorganic‐rich interphase from LPT electrolyte effectively suppresses structural degradation to ensure a fast dynamic behavior. The utilization of LPT electrolyte also greatly reduces the amount of heat released and the production of O 2 gas, which is favorable for addressing thermal runaway hazards. This screening strategy offers a practical approach for the design of flame‐retardant high‐voltage electrolytes.