Empty fruit bunch (EFB) utilization to produce valuable bio-chemicals is seen as an economical and sustainable alternative to waste management in palm oil industries. This work proposed an integrated biorefinery configuration of EFB valorization considering sustainability pillars—namely, economic, environmental, and safety criteria. Techno-economic analysis, life cycle assessment, and hazard identification ranking methods were used to estimate annual profit, global warming potential (GWP), fire explosion damage index (FEDI), and toxicity damage index (TDI) of the proposed integrated biorefinery. A multi-objective optimization problem was then formulated and solved for simultaneous maximization of profit and minimization of GWP, FEDI and TDI. The resulting Pareto-optimal solutions convey the trade-off among the economic, environmental, and safety performances. To choose one of these optimal solutions for implementation, a combined approach of fuzzy analytical hierarchy process and a technique for order preference by similarity to ideal solution was applied. For this selection, the economic criterion was more preferred, followed by the safety and environmental criterion; thus, the optimal solution selected for integrated biorefinery configuration had the highest annual profit, which was at the maximum capacity of 100 ton/h of EFB. It can fulfill the global demand of xylitol (by 55%), levulinic acid (by 98%), succinic acid (by 25%), guaiacol (by 90%), and vanillin (by 12%), and has annual profit, GWP, FEDI, and TDI of 932 M USD/year, 284 tonCO2-eq, 595, and 957, respectively.