BackgroundDermatophyte caused byTrichophyton mentagrophytesis a global disease with a growing prevalence that is difficult to cure.Perilla frutescens(L.) Britt. is an edible and medicinal plant. Ancient books of Traditional Chinese Medicine and modern pharmacological studies have shown that it has potential anti-fungi activity. This is the first study to explore the inhibitory effects of compounds fromP. frutescensonTrichophyton mentagrophytesand its mechanism of action coupled with the antifungal activity in vitro from network pharmacology, transcriptomics and proteomics.MethodsFive most potential inhibitory compounds against fungi inP. frutescenswas screened with network pharmacology. The antifungal activity of the candidates was detected by a broth microdilution method. Through in vitro antifungal assays screening the compound with efficacy, transcriptomics and proteomics were performed to investigate the pharmacological mechanisms of the effective compound againstTrichophyton mentagrophytes. Furthermore, the real-time polymerase chain reaction (PCR) was applied to verify the expression of genes.ResultsThe top five potential antifungal compounds inP. frutescensscreened by network pharmacology are: progesterone, luteolin, apigenin, ursolic acid and rosmarinic acid. In vitro antifungal assays showed that rosmarinic acid had a favorable inhibitory effect on fungi. The transcriptomic findings exhibited that the differentially expressed genes of fungus after rosmarinic acid intervention were mainly enriched in the carbon metabolism pathway, while the proteomic findings suggested that rosmarinic acid could inhibit the average growth ofTrichophyton mentagrophytesby interfering with the expression of enolase in the glycolysis pathway. Comparison of real-time PCR and transcriptomics results showed that the trends of gene expression in glycolytic, carbon metabolism and glutathione metabolic pathways were identical. The binding modes and interactions between rosmarinic acid and enolase were preliminary explored by molecular docking analysis.ConclusionThe key findings of the present study manifested that rosmarinic acid, a medicinal compound extracted fromP. frutescens, had pharmacological activity in inhibiting the growth ofTrichophyton mentagrophytesby affecting its enolase expression to reduce metabolism. Rosmarinic acid is expected to be an efficacious product for prevention and treatment of dermatophytes.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13020-023-00772-2.