Alismatis rhizoma (AR), the dried rhizome of Alisma orientale (Sam) Juzep, is effective in treating hyperlipidemia, but the mechanisms involved require further exploration. This study evaluated the hypolipidemic properties of AR using an integrated strategy combining network pharmacology with metabolomics and lipidomics. Firstly, a hyperlipidemia mouse model induced by a high-fat diet was established to evaluate the therapeutic effects of AR. Secondly, plasma metabolomics and lipidomics were used to identify differential metabolites and lipids, and metabolic pathway analysis was performed using MetaboAnalyst. Thirdly, network pharmacology, based on the metabolic profile of AR in vivo, was used to discover potential therapeutic targets. Finally, key targets were obtained through a compound-target-metabolite network, which was verified by molecular docking and quantitative real-time PCR (qPCR). Biochemistry analysis and histological examinations showed that AR exerted hypolipidemic effects on hyperlipidemic mice. Seventy potential biomarkers for the AR treatment of hyperlipidemia were identified by metabolomics and lipidomics, which were mainly involved in lipid metabolism, energy metabolism and amino acid metabolism. Eighteen potentially active compounds were identified in the plasma of mice after oral administration of AR, which were associated with 83 potential therapeutic targets. The PPAR signaling pathway was considered a crucial signaling pathway of AR against hyperlipidemia by KEGG analysis. The joint analysis showed that 6 upstream key targets were regulated by AR, including ALB, TNF, IL1B, MMP9, PPARA and PPARG. Molecular docking showed that active compounds of AR had high binding affinity with these key targets. qPCR further demonstrated that AR could reverse the mRNA expression of these key targets in hyperlipidemic mice. This study integrates network pharmacology with metabolomics and lipidomics to reveal the regulatory effects of AR on endogenous metabolites and validates key therapeutic targets, and represents the most systematic and in-depth study on the hypolipidemic activity of AR.