A general framework implementing process design, simulation, heat integration, and life cycle assessment (LCA) is illustrated to develop a sustainable route, which is particularly exploited to evaluate the environmental impacts of the p-xylene production from both generation biomass feedstocks. Noticeably, the lignocellulose-based p-xylene is comparable with the petroleum-based p-xylene, while the starch-based p-xylene appears less environmentally friendly. In the latter case, the cultivation and processing of maize starch and heating requirements dominate total environmental impacts. The main contributions for the lignocellulose-based p-xylene arise from the cultivation of biomass and the large requirements of nonrenewable chemicals (i.e., the makeup solvent (THF) and ethylene). Sensitivity analysis indicates that high selectivity is also favored to achieve better environmental performance, while the impacts of conversion are negligible and discovers a large variance from different biomass feedstocks. The uncertainties caused by the assumptions and developing technologies are assessed by uncertainty analysis.