Abstract: The reindustrialization of acetone–butanol–ethanol (ABE) fermentation is hampered by its significant production cost, linked to high product inhibition and low product yield. ABE fermentation can be significantly enhanced by integrating in situ liquid–liquid extraction. In this study, hybrid simulations using Excel® and ASPEN Plus® were performed based on solvent-dependent experimental data (product titer, yield and productivity) to consider the physiological response of the microorganism in specific extractive ABE fermentations, and to quantify the energy requirements and the economic improvement of the overall process. Four scenarios, based on two different solvents (2-butyl-1-octanol, 2B1O, and a vegetable oil, VO) applied in batch or fed-batch operation, were compared with the batch conventional process. Total energy demand decreased in all extractive configurations and the greatest energy savings (61%) were reached with the VO-based fed-batch operation. However, the highest profit increase was achieved with 2B1O in fed-batch mode, reducing the minimum butanol selling price by 29% over the base case, along with 34% savings in raw materials and 80% wastewater reduction. The techno–economical solvent-based comparative evaluation is a useful tool to identify key challenges to be tackled when revisiting ABE extractive fermentation. Graphical abstract: [Figure not available: see fulltext.]