Thermochemical process routes are promising technological routes to convert lignocellulosic biomass into biofuels with similar properties as fossil fuels. In a previous work (Ind. Eng. Chem. Res. 2018 57, 9925-9942), we have studied five base case processes for biofuel production with fixed process structures. This work presents an integrated methodology to consider new process structures for the optimal synthesis of lignocellulosic biomass-to-liquid (BtL) fuel production processes. Given that the five base cases showed not only a significant difference of production costs among the process sections but also distinct biofuel product profiles in terms of gasoline and diesel productivity, the current methodology is developed in two parts: part 1 presents the superstructure synthesis through the step-by-step definition of unit operations' possible interconnections to include all possible new process alternatives than base cases. The superstructure is developed based on the data collected from unit operations' rigorous simulation of the base cases. Part 2 presents the superstructure algorithm setup and optimization for the optimal synthesis of BtL process flowsheets with specified product profiles of gasoline and diesel productivity. Rigorous simulation results for process units and process sections are used in the superstructure formulation and its algorithm development. Three case studies have shown that the integrated methodology can generate new production processes with specified product profiles while having lower total manufacturing costs than base cases.