Mammalian B-cell lymphoma/leukemia 2 (Bcl-2) has cytoprotective effects against oxidative stress in yeast cells. This study showed that human Bcl-2 increased nerolidol production in an engineered Saccharomyces cerevisiae strain with higher cell viability and lower reactive oxygen species levels. Our previous study found that the overexpression of HAC1, the key regulator of endoplasmic reticulum stress, increased the nerolidol titer levels. Endoplasmic reticulum stress has crosstalk with oxidative stress. We thus investigated the coincident effect of the overexpression of BCL-2 and HAC1, and found that both of them changed the transcription of genes involved in the fatty acid metabolism pathway and resulted in increased nerolidol synthesis. The addition of 3 mM linoleic acid further increased the nerolidol titer to 725.5 mg/L. Finally, fed-batch fermentation was implemented and resulted in the accumulation of 15.5 g/L nerolidol. This study provides a simple and effective strategy for sesquiterpene production in engineered yeast.