One of the major obstacles of acetone–butanol–ethanol (ABE) fermentation from renewable biomass resources is the energy-intensive separation process. To decrease the energy demand of the ABE downstream separation processes, hybrid in situ separation system with conventional distillation is recognized as an effective method. However, in the distillation processes, the high reflux ratio of the ethanol column and the accumulation of ethanol on top of the water and butanol columns led to poor controllability and high operation cost of the distillations. In this study, vacuum distillation process which is based on a decanter-assisted ethanol–butanol–water recycle loop named E-TCD sequence was developed to improve the conventional separation sequence for ABE separation. The permeate of in situ pervaporation system was used as the feed. The distillation processes were simulated and optimized by iterative strategies. ABE mixture with acetone, butanol and ethanol concentrations of 115.8 g/L, 191.4 g/L and 17.8 g/L (the other composition was water) that obtained from fermentation–pervaporation integration process was used as the feed. A plant scaled to 1025 kg/h of ABE mixture was performed, and the product purities were 100 wt% of butanol, 99.7 wt% of acetone and 95 wt% of ethanol, respectively. Results showed that only 5.3 MJ/kg (of butanol) was required for ABE separation, which was only 37.54% of the energy cost in conventional distillation processes. Compared with the drawbacks of ethanol accumulation in butanol–water recycle loop and the extremely high recovery rate of ethanol in conventional distillation processes, simulation results obtained in the current work avoided the accumulation of ethanol based on the novel E-TCD sequence.