Abstract: To investigate the in vivo antioxidant activity and related mechanisms of Artemisia argyi leaf alcohol extract (ALE), this study evaluated the effects of Artemisia argyi leaf alcohol extract on the antioxidant enzyme activities and the mean lifespan of Caenorhabditis elegans (C. elegans) under oxidative stress. In addition, a variety of transgenic strains combined with molecular biological methods were utilized to explore the related molecular mechanisms. The results showed that pretreated with ALE significantly extended the mean lifespan of worms under oxidative stress by 13.21% (P=0.0002), 21.72% (P<0.0001) and 16.11% (P<0.0001) at concentrations of 50, 200, and 400 μg/mL, respectively. Moreover, ALE considerably increased the SOD, CAT activity and GSH levels of C. elegans (P<0.05). Furthermore, the nuclear proportion of SKN-1 was increased from 20.14% to 45.68% in LD1 strains when treated with 200 μg/mL ALE. Additionally, ALE significantly upregulated the expression of SKN-1 downstream target genes gcs-1, gst-4, sod-2 and ctl-1 (P<0.05). Besides, similar results were also observed in the expression of resistance proteins GCS-1 and GST-4. The improvement of in vivo antioxidant activity of ALE was related to the activation of SKN-1 signaling pathway. This study provides a theoretical basis for the application of Artemisia argyi leaf in alleviating oxidative stress damage.