Driven by the excessive consumption of fossil resources and environmental pollution concerns, a large amount of biorefinery research efforts have been made for converting lignocellulosic biomass into fuels and chemicals. Recently, a strategy termed “lignin-first,” which allows for realizing high-yield and high-selectivity aromatic monomers, is regarded as one of the best prospective strategies. This review summarizes recent research advances in lignin-first biorefinery, starting from the raw lignocellulose through lignin-first processing and moving to downstream processing pathways for intermediate compounds. In particular, for the core purpose of producing liquid fuels, the corresponding downstream processing strategies are discussed in detail. These are based on the structural properties of the intermediates derived from lignin-first biorefinery, including the catalytic conversion of lignin and its derivatives (aqueous phase system and pyrolysis system) and the cascade utilization of carbohydrate residues (fermentation, pyrolysis, and hydrothermal liquefaction). We conclude with current problems and potential solutions, as well as future perspectives on lignin-first biorefinery, which may provide the basis and reference for the efficient utilization of lignocellulosic biomass.