This work presents solutions for the holistic utilization of lignocellulosic biomass based on the “lignin-first” concept. Biomass is fractionated by employing γ-Valerolactone (GVL) andformaldehyde solvents to effectively extract and protect the lignin and xylose ingredients. The process flowsheet of a large scale biomass fractionation technology – recently validated at laboratory scale by Shuai et al. (2016a) – has been developed and simulated to test and build performance in use of energy, water and materials. The biorefinery value chain further integrates chemistries for the production of platform chemicals and biofuels (furfural, levulinic acid and lignin-aromatics), while the C6 sugars fraction is partially converted into GVL to offset any solvent losses. Energy integration and techno-economic analyses revealed 38–60% steam savings, 2.5–3.1 MW power cogeneration potential and 10–15 Μ€ annual profitability for the overall multiple-product biorefinery. Finally, a cradle-to-gate LCA approach identified environmental hot-spots (e.g. the use of THF in hydrotreatment) and estimated up to 11.1 kg_CO2eq emissions per kg of end-product.