Abstract: In this study, the flavonoids of Artemisia argyi leaf were extracted and identified. Subsequently, the lipid-lowering effects of Artemisia argyi leaf flavonoids extract (AALE) and its underlying mechanisms were investigated using a combination of the Caenorhabditis elegans (C. elegans) model and in vitro lipase inhibition assays. The results showed that AALE exhibited significant inhibitory activity against pancreatic lipase, with a half-maximal inhibitory concentration (IC₅₀) of 8.085±0.28 mg/mL, and this inhibition was non-competitive. Furthermore, AALE significantly reduced triglyceride (TG) levels in a high-fat nematode model (P<0.05). The TG content in the high-fat control group was 2.35 mmol/g, whereas in the treatment groups supplemented with 240 and 360 µg/mL of AALE, the TG levels decreased 37.45% and 34.04% (P<0.05), respectively. Further studies revealed that AALE significantly downregulated the expression of key genes involved in fat synthesis pathways in nematodes, including fat-6, fat-7, pod-2, and fasn-1, while upregulating the expression of acs-2, a gene associated with lipolysis. Moreover, the effect of AALE in reducing TG levels was dependent on the critical fatty acid synthesis genes fat-6 and fat-7. In conclusion, AALE can inhibit pancreatic lipase activity and reduce the TG content in nematodes, demonstrating a good lipid-lowering effect. This study provides a theoretical basis for the high-value utilization of Artemisia argyi.