Process scale-up is a critical factor for realizing the industrial-scale production of docosahexaenoic acid (DHA). To improve the efficiency of scale-up, a strategy based on computational fluid dynamics analysis and investigation of microbial physiological properties was developed. We first investigated the physiological response of Schizochytrium sp. to different scale bioreactors, and the results indicated that a homogeneous culture environment was beneficial for cell growth and DHA biosynthesis. Fluid dynamics of different scale bioreactors were further investigated and impeller combinations were designed and optimized by computational methods to obtain a homogeneous culture environmental in a 7000 L bioreactor. The results showed that the optimal impeller combination could provide a more balanced culture environment, similar to lab-scale bioreactors. When the optimal strategy was used to scale-up the DHA fermentation, the biomass, DHA concentration, DHA percentage in biomass and DHA productivity reached 128.3 g/L, 39.2 g/L, 30.5%, 326.5 mg/(L h), respectively. This study thus introduces a highly efficient and economical scale-up strategy for DHA production using Schizochytrium sp. (C) 2017 Elsevier Ltd. All rights reserved.