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Background: Prostate cancer (PCa) is one of the malignant tumors that seriously affect the health of middle-aged and older men. Chinese medicinal herbs have great potential in tumor therapy with less toxic side effects. 6-C-methylquercetin in the folk medicine Baeckea frutescens, has a good inhibitory effect on human prostate cancer cells (PC3), but its effect and mechanism of anti-PCa have not been elucidated., Purpose: This study aimed to investigate the antitumor effect of 6-C-methylquercetin on PCa and its molecular mechanism., Methods: Network pharmacology was employed to predict the potential targets and pathways of 6-C-methylquercetin acting on PCa, and molecular docking and molecular dynamics simulations were used to analyze the interactions between 6-C-methylquercetin and key target proteins. CCK8, flow cytometry, wound healing, transwell, RT-qPCR, and western blot assay were performed to elucidate the effect of 6-C-methylquercetin on the proliferation, apoptosis, cycle, migration and invasion of PC3 cells, and revealed its regulations on the ErbB/PI3K/AKT pathway. For in vivo experiments, the nude mouse PC3 xenograft model was used, H&E staining, TUNEL, and immunofluorescence assay were performed on tumor tissues, and the biosafety was evaluated by blood routine examination and liver and kidney function tests., Results: Network pharmacological analysis and computational simulations revealed that 6-C-methylquercetin acted on PCa through the ErbBs and PI3K/AKT pathway, and 6-C-methylquercetin had a strong binding affinity for these key node proteins. In vitro experiments demonstrated that 6-C-methylquercetin inhibited the proliferation, migration and invasion of PC3 cells, affected the cell cycle, and induced apoptosis, by suppressing the ErbB/PI3K/AKT pathway activity. Animal experiments showed that 6-C-methylquercetin inhibited the progression of prostate cancer in tumor xenograft mice with a good in vivo biosafety., Conclusion: The study first revealed the anti-PCa potential of 6-C-methylquercetin, which may involve the regulation of the ErbB/PI3K/AKT pathway, but its direct targets and specific therapeutic mechanism need to be further explored. These findings suggested that 6-C-methylquercetin had the potential to suppress the development of PCa, and provided a scientific basis for the development and utilization of C-methylated flavonoid compounds from B. frutescens., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier GmbH. All rights reserved.)