Abstract: OBJECTIVE To explore the possible molecular mechanism of licorice flavonoids anti-acne based on network pharmacology, QSAR and molecular docking, and to provide reference for the preparation of its transdermal preparations. METHODS Firstly, the key active ingredients and targets of licorice flavonoids anti-acne through network pharmacology were screened out. Then, the optimal QSAR pharmacophore model for the activity of licorice flavonoids was constructed by the HipHop method, and the pharmacophore that might play a decisive therapeutic role was deduced. Finally, the pharmacophore was verified by molecular docking. RESULTS Network pharmacology studies showed that 7-hydroxyflavone, glabrolide, 9S,13R-12- oxophytodienoic acid, naringenin and 4'-methoxyflavone were key anti-acne active components in licorice flavonoids, and CYP19A1, ALOX5 and ESR1 are key anti-acne targets. The QSAR pharmacophore model studies showed that the optimal pharmacophore of licorice flavonoids consists of one hydrophobic group and two hydrogen bond acceptor groups. The molecular docking study showed that the active compounds screened by network pharmacology had a good affinity with the target protein, and the optimal pharmacophore model constructed by QSAR might be the decisive therapeutic pharmacophore of licorice flavonoids in anti-acne. CONCLUSION This study successfully established the structure-activity relationship between the structural properties and anti-acne activity of licorice flavonoids, which provides theoretical guidance for the development and clinical application of traditional Chinese medicine transdermal preparations.