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<i>Artemisia japonica</i> Thunb. has been used as a traditional Chinese medicine and a vegetable for thousands of years in China. However, there are few reports on the chemical composition and biological activity of its leaves. Thus, this study aimed to evaluate the chemical composition, antioxidant and anti-inflammatory effects of water extracts of <i>A. japonica</i> leaves and their underlying mechanisms. A total of 48 compounds were identified in the water extract using UPLC-QTOF-MS² analysis, with phenolic acids, particularly chlorogenic acid compounds, being the predominant components. The ethyl acetate fraction (EAF) contained most of the total phenolic content (385.4217 mg GAE/g) and displayed superior antioxidant capacity with the IC_50DPPH•, IC_50ABTS•+, and OD_{0.5reducing power} at 10.987 μg/mL, 43.630 μg/mL and 26.883 μg/mL, respectively. Furthermore, EAF demonstrated potent antioxidant and anti-inflammatory effects in LPS-induced RAW264.7 cells by upregulating the Nrf2/HO-1 signal pathway. These findings highlight that <i>A. japonica</i> leaves possess remarkable abilities to mitigate inflammation and oxidative stress, suggesting their potential utilization as medicinal agents and food additives for promoting human health.