Saccharomyces cerevisiae × Saccharomyces kudriavzevii hybrids are typically used for white wine fermentation because of their cryotolerance. One group of these hybrids presents a unique ability to release thiol varietal aroma products as well as excessive amounts of acetic acid under specific conditions, which is detrimental for wine organoleptic quality. The aim of this work is to better assess the effects of lipids, sugar concentrations and temperature on the production of acetic acid and thiols during wine fermentation. To this end, we used a Box–Behnken experimental design and response surface modeling on the production of acetic acid and thiols in S. cerevisiae × S. kudriavzevii hybrids from the Eg8 family during fermentation of a synthetic must. We showed that these hybrids produced lower levels of acetic acid when the initial lipid concentration was increased, whereas they produced greater levels when the initial sugar concentration was high. Moreover, we found that lipids had a positive impact on the final concentrations of 4-methyl-4-mercaptopentan-2-one and 3-mercaptohexan-1-ol (3MH), giving box tree and citrus flavors, respectively. The increase of 3MH was concomitant with a decrease of 3-mercaptohexyl acetate (3MHA) characterized by a passion fruit aroma, indicating that lipid addition reduces the rate of 3MH acetylation into 3MHA. These results highlight the key role of lipid management in acetic acid metabolism and thiol release by S. cerevisiae × S. kudriavzevii hybrids and underline its technological interest in alcoholic fermentation to avoid the overproduction of volatile acidity while favoring the release of volatile thiols.