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The sesquiterpene (−)-α-bisabolol has been shown to have antibacterial, antiseptic, and anti-inflammatory activities, as well as skin-soothing properties, which has led to its wide use in cosmetics. However, the current production of (−)-α-bisabolol via steam-distillation of plants is not sustainable and cannot meet the increasing market demand. In the present study, a sustainable strategy for (−)-α-bisabolol production was developed by constructing a Yarrowia lipolytica cell factory. The oleaginous yeast Y. lipolytica has a native mevalonate pathway and strong acetyl-CoA flux, which can supply adequate precursors for (−)-α-bisabolol production. The endogenous mevalonate pathway and heterologous (−)-α-bisabolol synthesis pathway were optimized by strengthening the rate-limiting enzymes, downregulating competing pathway, as well as balancing the distribution of the common precursor acetyl-CoA between endogenous lipids and heterologous (−)-α-bisabolol synthesis by strengthening the β-oxidation pathway. Finally, (−)-α-bisabolol production of up to 364.23 mg L−1 was achieved in batch culture. This sustainable method has potential for industrial (−)-α-bisabolol production. [ABSTRACT FROM AUTHOR]