Lignin valorization is severely constrained by its inherent structural heterogeneity and the limitations of empirical fractionation methods. To address this, we developed a rational solvent design framework integrating Hansen Solubility Parameter clustering with Globally Harmonized System safety screening. This approach shifts the paradigm from uncertain quantitative yield prediction to qualitative property-based classification. Applying this framework, we identified ethyl acetate and ethyl lactate as an optimal eco-friendly binary pair based on the design principle that structural similarity ensures miscibility while functional complementarity enables selectivity. The resulting binary system allowed for continuous molecular weight control (1080–4010 Da) through simple ratio tuning. A streamlined three-step sequential fractionation process was subsequently developed, achieving 88.74% total recovery with unprecedented yield uniformity. The fractionated lignin exhibited significantly improved homogeneity, with polydispersity index (PDI) values reduced to 1.76–2.20 and possessed tailored hydroxyl group compositions suitable for high-value applications. Comparative analysis confirmed the method’s superior performance in process efficiency and molecular weight separation against benchmark studies. Beyond demonstrating an effective solvent system, this work establishes a systematic design framework transferable to other lignin types, advancing lignin valorization from empirical practice to rational engineering.