ETHNOPHARMACOLOGICAL RELEVANCE: Total flavones of Epimedium (TFE) is the main active ingredient in Herba Epimedii, which is a well-known Chinese herbal medicine that is widely used to treat certain age-related diseases in oriental countries. AIM OF THE STUDY: The aim of this work was to investigate the anti-aging properties of TFE related to lipid metabolism. MATERIALS AND METHODS: Both transcriptomics and metabonomics were applied in this work to investigate the anti-aging properties of TFE. Microarray and LC-MS analysis were conducted on liver samples of three groups of rats, including young (4 months), old (24 months), and old rats administrated TFE. RESULTS: Transcriptomics analysis highlighted 287 transcripts related to the anti-aging effect of TFE, in which the expression ratio of 18 genes regulating lipid metabolism, including HMGCS1 and NR1H3, returned to normal levels after TFE treatment. In addition, 24 aging-related metabolites were discovered in a metabonomics study, and 15 of these were structurally identified, including palmitic amide, linoleamide, and oleamide. Bioinformatics and integral data analysis on the results of the transcriptomics and metabonomics suggest the involvement of 12 key metabolic pathways, half of which are highly related to lipid metabolism. CONCLUSIONS: This study demonstrates that the role played by TFE in the lipid metabolism of aging rats is multifaceted and multi-layered.