Phenylethanol glycosides (PhGs) constitute crucial bioactive compounds in Cistanche Herba. However, their bioavailability is notably low. Research indicates that intestinal flora can metabolize PhGs into small polyphenols, enhancing bioavailability and pharmacological activities. In this paper, for the first time, a single strain, Beauveria bassiana, was found to be effective in converting PhGs from the crude extract of Cistanche tubulosa into small molecule polyphenols like hydroxytyrosol (HT), decaffeoylacteoside (HT-glu-rha), and caffeic acid through fermentation. We assessed the impact of pre- and post-fermentation on Propionibacterium acnes-induced acne related to a western diet through in vitro cellular experiments. Both pre- and post-fermentation exhibited efficacy in inhibiting inflammation, oxidative stress, and mitochondrial membrane damage in P. acnes-induced HaCaT. Moreover, post-fermentation, unlike pre-fermentation, displayed stronger and a dose-dependent reduction in insulin-stimulated lipid synthesis in sebaceous gland cells. To further understand the increased efficacy of fermentation in inhibiting lipid synthesis, we investigated HT-glu-rha, the predominant small molecules produced during fermentation. It was shown that the compound inhibited lipid synthesis by decreasing gene expression of sterol regulatory element binding transcription factor 1 (SREBP-1) and peroxisome proliferator activated receptor gamma (PPARγ) in sebaceous gland cells.