Colombia is experiencing significant growth in its agricultural areas, its diverse production chains make the country an excellent candidate in the development of biorefineries, and as a result, there is an increasing need to take full advantage of biomass and obtain high value-added by-products from waste. In this sense, biorefineries are presented as a great alternative for the use of biomass; however, the methodologies of biorefinery synthesis lack a parameter that limits the growth of production lines under incremental exergetic and economic returns. This research develops a biorefinery synthesis methodology using an African palm biorefinery as a case study; a novel approach is developed to facilitate a stop criterion for biorefinery expansion through a combined consideration of economic incremental returns (IROI) and exegetical returns of investment (ExROI), avoiding unnecessary plant expansions or new processes that are not profitable or adequate in terms of useful energy. The development of this methodology required simulations in Aspen Plus software and technical-economic and exergetic evaluation with an incremental approach of four scenarios in Excel. The base case is palm oil production from African palm clusters. The second case includes the production of palm kernel oil and palm cake from residues. The third case implements the production of hydrogen based on other residues from the base case. The last case study incorporates the preceding case and the addition of biodiesel and glycerin production from palm oil. Case 3 exhibits a higher economic performance with an IROI of 42.98%; in terms of exergy, case 2 exhibits considerable improvements over the base case, with an ExROI of 158%. A parameter called the exergo-economic weighted incremental return on investment (IExWROI) was obtained, evidencing a 75% improvement in case 2 compared to the base case. The new indicator aims to provide a more comprehensive approach to biorefinery design by optimization of economic and exergetic returns, contributing a new alternative for decision-making in regard to plant design, plant expansion projects, and implementation of subprocesses.