This work presents solutions for the holistic utilization of lignocellulosic biomass based on the “lignin-first” concept. Biomass is fractionated by means of γ-Valerolactone (GVL) and Formaldehyde solvents to effectively extract and protect lignin and xylose ingredients. The process flowsheet and simulation of a large scale biomass fractionation technology – recently validated in laboratory scale by Shuai et al. (2016) – are developed to test and build performance in use of energy, water and materials. The biorefinery value chain additionally 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 solvent losses. Finally, energy integration and techno-economic analysis resulted in up to 6% steam savings, 1.8 MW power cogeneration and 37 Μ€/yr net revenues for the overall biorefinery.